molecular glue

Molecular glue compounds are typically small molecules that facilitate interactions between proteins by stabilizing or inducing protein–protein interactions (PPIs). These compounds often bind to specific binding sites on a target protein and alter its surface conformation, promoting interactions with other proteins that would not normally associate. By reshaping protein surfaces, molecular glues can stabilize protein complexes, reducing their tendency to dissociate, and thus modulate essential cellular functions, many of which rely on dynamic protein assemblies. Through this mechanism, molecular glues can alter the function, localization, or stability of target proteins, offering valuable applications in both therapeutic and research contexts.

Unlike PROTACs, which are bifunctional and physically tether the target to an E3 ubiquitin ligase, molecular glues induce or enhance PPIs between the ligase and the substrate by binding at existing or latent interaction surfaces.{{cite journal | vauthors = Simonetta KR, Taygerly J, Boyle K, Basham SE, Padovani C, Lou Y, Cummins TJ, Yung SL, von Soly SK, Kayser F, Kuriyan J, Rape M, Cardozo M, Gallop MA, Bence NF, Barsanti PA, Saha A | title = Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction | journal = Nature Communications | volume = 10 | issue = 1 | pages = 1402 | date = March 2019 | pmid = 30926793 | pmc = 6441019 | doi = 10.1038/s41467-019-09358-9 | bibcode = 2019NatCo..10.1402S }} This mechanism allows for selective targeting of proteins, including those previously considered "undruggable."

A notable example involves small molecules that promote the interaction between the oncogenic transcription factor β-Catenin and the E3 ligase SCFβ-TrCP. These molecules function as molecular glues by enhancing the native PPI interface, resulting in increased ubiquitylation and subsequent degradation of mutant β-Catenin both in vitro and in cellular models. Unlike PROTACs, which require two separate binding moieties, these monovalent molecules insert directly into the PPI interface, simultaneously optimizing contacts with both substrate and ligase within a single chemical entity.

Molecular glues are especially advantageous for degrading non-ligandable targets, as they exploit naturally complementary protein surfaces to induce degradation without requiring high-affinity ligands for the target protein. Although many molecular glues have historically been discovered serendipitously and characterized retrospectively, newer approaches now aim to identify them prospectively through systematic chemical profiling.{{cite journal |vauthors=den Besten W, Lipford JR |date=November 2020 |title=Prospecting for molecular glues |journal=Nature Chemical Biology |volume=16 |issue=11 |pages=1157–1158 |doi=10.1038/s41589-020-0620-z |pmid=32747810 |s2cid=220947901}}

For example, the compound CR8 was identified through correlation analysis as a molecular glue that promotes ubiquitination and degradation of specific targets via a top-down screening approach.{{cite journal | vauthors = Tian C, Burgess K | title = PROTAC Compatibilities, Degrading Cell-Surface Receptors, and the Sticky Problem of Finding a Molecular Glue | journal = ChemMedChem | volume = 16 | issue = 2 | pages = 316–318 | date = January 2021 | pmid = 33112038 | doi = 10.1002/cmdc.202000683 | s2cid = 225100015 }} This highlights the broader potential of small molecules, beyond PROTACs, in targeted protein degradation strategies.

There is also growing evidence that molecular glues can stabilize interactions beyond protein–protein pairs, including protein–RNA{{cite journal | vauthors = Childs-Disney JL, Yang X, Gibaut QM, Tong Y, Batey RT, Disney MD | title = Targeting RNA structures with small molecules | journal = Nature Reviews. Drug Discovery | volume = 21 | issue = 10 | pages = 736–762 | date = October 2022 | pmid = 35941229 | pmc = 9360655 | doi = 10.1038/s41573-022-00521-4 }} and protein–lipid complexes.{{cite journal | vauthors = Pahil KS, Gilman MS, Baidin V, Clairfeuille T, Mattei P, Bieniossek C, Dey F, Muri D, Baettig R, Lobritz M, Bradley K, Kruse AC, Kahne D | title = A new antibiotic traps lipopolysaccharide in its intermembrane transporter | journal = Nature | volume = 625 | issue = 7995 | pages = 572–577 | date = January 2024 | pmid = 38172635 | pmc = 10794137 | doi = 10.1038/s41586-023-06799-7 | doi-access = free | bibcode = 2024Natur.625..572P }}

Molecular glues are categorized into functional types based on their mechanisms of modulating protein-protein interactions (PPIs): stabilization of non-native (type I) or native (type II) protein-protein interactions.

Type I molecular glues induce non-native protein-protein interactions that physically block, or "shield," a protein’s normal endogenous activity. Rather than promoting protein degradation, these compounds typically stabilize inactive conformations{{cite journal | vauthors = Soini L, Leysen S, Davis J, Ottmann C | title = Molecular glues to stabilise protein-protein interactions | journal = Current Opinion in Chemical Biology | volume = 69 | issue = | pages = 102169 | date = August 2022 | pmid = 35749929 | doi = 10.1016/j.cbpa.2022.102169 }} or mask functional regions of the target protein, thereby preventing it from participating in its usual biological processes. This can include blocking active sites, disrupting ligand binding, or interfering with native protein–protein interactions.{{cite journal | vauthors = Dewey JA, Delalande C, Azizi SA, Lu V, Antonopoulos D, Babnigg G | title = Molecular Glue Discovery: Current and Future Approaches | journal = Journal of Medicinal Chemistry | volume = 66 | issue = 14 | pages = 9278–9296 | date = July 2023 | pmid = 37437222 | pmc = 10805529 | doi = 10.1021/acs.jmedchem.3c00449 }}{{cite journal | vauthors = Zhao L, Zhao J, Zhong K, Tong A, Jia D | title = Targeted protein degradation: mechanisms, strategies and application | journal = Signal Transduction and Targeted Therapy | volume = 7 | issue = 1 | pages = 113 | date = April 2022 | pmid = 35379777 | pmc = 8977435 | doi = 10.1038/s41392-022-00966-4 }}

One example is the immunosuppressant rapamycin, which forms a ternary complex with FKBP12 and the kinase mTOR, resulting in inhibition of mTOR activity. Another is cyclosporin A, which bridges cyclophilin A and calcineurin, leading to inhibition of calcineurin’s phosphatase function. These cases illustrate how Type I molecular glues can modulate protein function by enforcing artificial protein interactions that hinder normal activity.

Type II molecular glues stabilize endogenous protein-protein interactions by altering protein conformation or dynamics. They can either inhibit or enhance activity by locking proteins into specific states. One example is lenalidomide (an immunomodulatory drug), which binds cereblon (CRBN) and reprograms it to degrade transcription factors like IKZF1/IKZF3 in multiple myeloma. Other examples include tafamidis that stabilizes transthyretin (TTR) tetramers to prevent amyloid fibril formation in neurodegenerative diseases and paclitaxel that stabilizes microtubule polymers, blocking disassembly and inhibiting cancer cell division

Molecular glues employ two primary mechanisms to modulate protein-protein interactions (PPIs): allosteric regulation and direct bridging. Allosteric mechanisms dominate therapeutic applications of molecular glues because of their versatility in targeting diverse proteins and pathways.{{cite journal | vauthors = Deutscher RC, Meyners C, Repity ML, Sugiarto WO, Kolos JM, Maciel EV, Heymann T, Geiger TM, Knapp S, Lermyte F, Hausch F | title = Discovery of fully synthetic FKBP12-mTOR molecular glues | journal = Chemical Science | volume = 16 | issue = 10 | pages = 4256–4263 | date = March 2025 | pmid = 39916884 | pmc = 11796051 | doi = 10.1039/d4sc06917j | url = }}

In allosteric regulation, molecular glues bind to one protein, inducing conformational changes that create or stabilize novel interaction surfaces, enabling the recruitment of a second protein.{{cite journal | vauthors = Nada H, Choi Y, Kim S, Jeong KS, Meanwell NA, Lee K | title = New insights into protein-protein interaction modulators in drug discovery and therapeutic advance | journal = Signal Transduction and Targeted Therapy | volume = 9 | issue = 1 | pages = 341 | date = December 2024 | pmid = 39638817 | pmc = 11621763 | doi = 10.1038/s41392-024-02036-3 }} For example, lenalidomide binds to the E3 ligase cereblon (CRBN), remodeling its surface to recruit neo-substrates such as IKZF1/IKZF3 for ubiquitination and subsequent degradation.{{cite journal | vauthors = Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S, Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R | title = Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide | journal = Leukemia | volume = 26 | issue = 11 | pages = 2326–35 | date = November 2012 | pmid = 22552008 | pmc = 3496085 | doi = 10.1038/leu.2012.119 }} Similarly, CC-885 binds CRBN and induces the degradation of GSPT1 by stabilizing a ternary complex between CRBN, GSPT1, and the molecular glue.{{cite journal | vauthors = Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, Fang W, Wang NY, Nguyen D, Houston J, Carmel G, Tran T, Riley M, Nosaka L, Lander GC, Gaidarova S, Xu S, Ruchelman AL, Handa H, Carmichael J, Daniel TO, Cathers BE, Lopez-Girona A, Chamberlain PP | title = A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase | journal = Nature | volume = 535 | issue = 7611 | pages = 252–7 | date = July 2016 | pmid = 27338790 | doi = 10.1038/nature18611 }}

In contrast, direct bridging involves the glue physically linking two proteins at their interface. For instance, rapamycin bridges FKBP12 and mTOR by binding to both proteins simultaneously, forming a ternary complex that inhibits mTOR’s kinase activity.{{cite journal | vauthors = Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP | title = mTOR kinase structure, mechanism and regulation | journal = Nature | volume = 497 | issue = 7448 | pages = 217–23 | date = May 2013 | pmid = 23636326 | pmc = 4512754 | doi = 10.1038/nature12122 | bibcode = 2013Natur.497..217Y }} While direct bridging is observed in some cases, allosteric modulation is far more common in molecular glues due to its ability to exploit dynamic protein surfaces and induce novel interactions without requiring pre-existing binding pockets.

The ability of molecular glues to selectively degrade disease-relevant proteins has significant implications for drug discovery, particularly in the context of "undruggable" targets. Their monovalent nature and reliance on endogenous PPIs make them especially appealing for therapeutic development.

Compared to traditional small molecule drugs, molecular glues offer several advantages, including lower molecular weight, improved cell permeability, and favorable oral bioavailability. These properties align with the "Five Rules for Drugs" and may enable more efficient delivery and distribution in vivo.

In contrast, PROTACs—though similarly used for targeted protein degradation—often face challenges such as high molecular weight, reduced cell permeability, and poor pharmacokinetic profiles, which can hinder their clinical development.

Several therapeutic molecular glues have been developed to target proteins involved in cancer and other diseases. For instance, small molecule degraders of BCL6 and Cyclin K exploit both ligand-binding and PPI surfaces to drive the formation of ternary complexes with E3 ligases.{{cite journal | vauthors = Kozicka Z, Thomä NH | title = Haven't got a glue: Protein surface variation for the design of molecular glue degraders | journal = Cell Chemical Biology | volume = 28 | issue = 7 | pages = 1032–1047 | date = July 2021 | pmid = 33930325 | doi = 10.1016/j.chembiol.2021.04.009 | doi-access = free }} These compounds, typically under 500 Da, promote tight binding between ligase and neosubstrate in the presence of the glue and demonstrate high potency in cellular models.

As research continues to uncover new targets and refine discovery approaches, molecular glues are expected to play an increasingly important role in precision medicine and targeted degradation therapies.

Molecular glue compounds have demonstrated significant potential in cancer treatment by influencing protein-protein interactions (PPIs) and subsequently modulating pathways promoting cancer growth. These compounds act as targeted protein degraders, contributing to the development of innovative cancer therapies.{{cite journal | vauthors = Li F, Aljahdali IA, Ling X | title = Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein-Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases | journal = International Journal of Molecular Sciences | volume = 23 | issue = 11 | pages = 6206 | date = June 2022 | pmid = 35682885 | pmc = 9181451 | doi = 10.3390/ijms23116206 | doi-access = free }} The high efficacy of small-molecule molecular glue compounds in cancer treatment is notable, as they can interact with and control multiple key protein targets involved in cancer etiology. This approach, with its wider range of action and ability to target "undruggable" proteins, holds promise for overcoming drug resistance and changing the landscape of drug development in cancer therapy.

Molecular glue compounds are being explored for their potential in influencing protein interactions associated with neurodegenerative diseases such as Alzheimer's and Parkinson's. By modulating these interactions, researchers aim to develop treatments that could slow or prevent the progression of these diseases. Additionally, the versatility of small-molecule molecular glue compounds in targeting various proteins implicated in disease mechanisms provides a valuable avenue for unraveling the complexities of neurodegenerative disorders.

Molecular glue compounds, particularly those involved in targeted protein degradation (TPD), offer a novel strategy for inhibiting viral protein interactions and combating viral infections.{{cite journal | vauthors = Chakravarty A, Yang PL | title = Targeted protein degradation as an antiviral approach | journal = Antiviral Research | volume = 210 | pages = 105480 | date = February 2023 | pmid = 36567024 | pmc = 10178900 | doi = 10.1016/j.antiviral.2022.105480 | series = Special Issue in Honor of Dr. Mike Bray on his retirement as the Editor-in-Chief of Antiviral Research }} Unlike traditional direct-acting antivirals (DAAs), TPD-based molecules exert their pharmacological activity through event-driven mechanisms, inducing target degradation. This unique approach can lead to prolonged pharmacodynamic efficacy with lower pharmacokinetic exposure, potentially reducing toxicity and the risk of antiviral resistance. The protein-protein interactions induced by TPD molecules may also enhance selectivity, making them a promising avenue for antiviral research.

Molecular glue serves as a valuable tool in chemical biology, enabling scientists to manipulate and understand protein functions and interactions in a controlled manner. The emergence of targeted protein degradation as a modality in drug discovery has further expanded the applications of molecular glue in chemical biology. The ability of small-molecule molecular glue compounds to induce iterative cycles of target degradation provides researchers with a powerful method for studying protein-protein interactions and opens avenues for drug development in various human diseases.

Induce non-native PPIs to block or inhibit target activity without degradation:

• Cyclosporin (Cyclophilin A-Calcineurin): Bridges cyclophilin A and calcineurin, inhibiting phosphatase activity via steric hindrance.{{cite journal | vauthors = Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL | title = Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes | journal = Cell | volume = 66 | issue = 4 | pages = 807–815 | date = August 1991 | pmid = 1715244 | doi = 10.1016/0092-8674(91)90124-h }}
• RMC-7977 (Cyclophilin A-KRAS): Stabilizes a ternary complex (CYPA-KRAS-compound) to block KRAS-effector interactions, inhibiting downstream signaling without degradation.{{cite journal | vauthors = Schulze CJ, Seamon KJ, Zhao Y, Yang YC, Cregg J, Kim D, Tomlinson A, Choy TJ, Wang Z, Sang B, Pourfarjam Y, Lucas J, Cuevas-Navarro A, Ayala-Santos C, Vides A, Li C, Marquez A, Zhong M, Vemulapalli V, Weller C, Gould A, Whalen DM, Salvador A, Milin A, Saldajeno-Concar M, Dinglasan N, Chen A, Evans J, Knox JE, Koltun ES, Singh M, Nichols R, Wildes D, Gill AL, Smith JA, Lito P | title = Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS | journal = Science | volume = 381 | issue = 6659 | pages = 794–799 | date = August 2023 | pmid = 37590355 | pmc = 10474815 | doi = 10.1126/science.adg9652 | bibcode = 2023Sci...381..794S }}{{cite journal | vauthors = Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JA, Wildes D, Singh M | title = Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy | journal = Nature | volume = 629 | issue = 8013 | pages = 919–926 | date = May 2024 | pmid = 38589574 | pmc = 11111408 | doi = 10.1038/s41586-024-07205-6 | bibcode = 2024Natur.629..919H }}
• FK506 (FK506 (tacrolimus)) (FKBP12-Calcineurin): Forms a ternary complex with FKBP12 and calcineurin, suppressing phosphatase activity to prevent T-cell activation.
• Rapamycin (FKBP12-mTOR): Bridges FKBP12 and mTOR’s FRB domain, inhibiting kinase activity by blocking substrate access.{{cite journal | vauthors = Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL | title = A mammalian protein targeted by G1-arresting rapamycin-receptor complex | journal = Nature | volume = 369 | issue = 6483 | pages = 756–758 | date = June 1994 | pmid = 8008069 | doi = 10.1038/369756a0 | bibcode = 1994Natur.369..756B }}{{cite journal | vauthors = Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH | title = RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs | journal = Cell | volume = 78 | issue = 1 | pages = 35–43 | date = July 1994 | pmid = 7518356 | doi = 10.1016/0092-8674(94)90570-3 }}
• WDB002 (FKBP12-CEP250): Induces FKBP12-CEP250 interaction to inhibit centrosome amplification without degradation.{{cite journal | vauthors = Shigdel UK, Lee SJ, Sowa ME, Bowman BR, Robison K, Zhou M, Pua KH, Stiles DT, Blodgett JA, Udwary DW, Rajczewski AT, Mann AS, Mostafavi S, Hardy T, Arya S, Weng Z, Stewart M, Kenyon K, Morgenstern JP, Pan E, Gray DC, Pollock RM, Fry AM, Klausner RD, Townson SA, Verdine GL | title = Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 29 | pages = 17195–17203 | date = July 2020 | pmid = 32606248 | pmc = 7382241 | doi = 10.1073/pnas.2006560117 | doi-access = free | bibcode = 2020PNAS..11717195S }}
• NST-628 (RAF-MEK): Nondegrading glue that blocks RAF-MEK interactions, preventing MEK phosphorylation.{{cite journal | vauthors = Ryan MB, Quade B, Schenk N, Fang Z, Zingg M, Cohen SE, Swalm BM, Li C, Özen A, Ye C, Ritorto MS, Huang X, Dar AC, Han Y, Hoeflich KP, Hale M, Hagel M | title = The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers | journal = Cancer Discovery | volume = 14 | issue = 7 | pages = 1190–1205 | date = July 2024 | pmid = 38588399 | pmc = 11215411 | doi = 10.1158/2159-8290.CD-24-0139 }}
• NVS-STG2 (STING): Activates STING by binding between dimers but does not degrade the protein.{{cite journal | vauthors = Li J, Canham SM, Wu H, Henault M, Chen L, Liu G, Chen Y, Yu G, Miller HR, Hornak V, Brittain SM, Michaud GA, Tutter A, Broom W, Digan ME, McWhirter SM, Sivick KE, Pham HT, Chen CH, Tria GS, McKenna JM, Schirle M, Mao X, Nicholson TB, Wang Y, Jenkins JL, Jain RK, Tallarico JA, Patel SJ, Zheng L, Ross NT, Cho CY, Zhang X, Bai XC, Feng Y | title = Activation of human STING by a molecular glue-like compound | journal = Nature Chemical Biology | volume = 20 | issue = 3 | pages = 365–372 | date = March 2024 | pmid = 37828400 | pmc = 10907298 | doi = 10.1038/s41589-023-01434-y }}

Redirect or stabilize PPIs to induce target degradation.

• Auxin (TIR1-Aux/IAA): Promotes TIR1-Aux/IAA binding, leading to Aux/IAA ubiquitination and degradation.
• BIO-2007817 (Parkin-phosphoubiquitin): Enhances Parkin-phosphoubiquitin interactions to promote substrate degradation (assumed degradative mechanism).{{cite journal | vauthors = Sauvé V, Stefan E, Croteau N, Goiran T, Fakih R, Bansal N, Hadzipasic A, Fang J, Murugan P, Chen S, Fon EA, Hirst WD, Silvian LF, Trempe JF, Gehring K | title = Activation of parkin by a molecular glue | journal = Nature Communications | volume = 15 | issue = 1 | pages = 7707 | date = September 2024 | pmid = 39300082 | pmc = 11412986 | doi = 10.1038/s41467-024-51889-3 | bibcode = 2024NatCo..15.7707S }}
• 14-3-3/ERα Glues: Stabilize ERα-14-3-3 interactions, leading to ERα degradation (common degradative mechanism for 14-3-3 glues).{{cite journal | vauthors = Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR | title = Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments | journal = Journal of the American Chemical Society | volume = 145 | issue = 37 | pages = 20328–20343 | date = September 2023 | pmid = 37676236 | pmc = 10515640 | doi = 10.1021/jacs.3c05161 | bibcode = 2023JAChS.14520328K }}

CRBN-Based Degraders:

• Lenalidomide [CRBN-IKZF1, IKZF3, CK1α] Reprogram CRBN to degrade transcription factors.{{cite journal | vauthors = Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL | title = Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells | journal = Science | volume = 343 | issue = 6168 | pages = 301–305 | date = January 2014 | pmid = 24292625 | pmc = 4077049 | doi = 10.1126/science.1244851 | bibcode = 2014Sci...343..301K }}{{cite journal | vauthors = Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG | title = The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins | journal = Science | volume = 343 | issue = 6168 | pages = 305–309 | date = January 2014 | pmid = 24292623 | pmc = 4070318 | doi = 10.1126/science.1244917 | bibcode = 2014Sci...343..305L }}{{cite journal | vauthors = Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, Chamberlain PP, Mani DR, Man HW, Gandhi AK, Svinkina T, Schneider RK, McConkey M, Järås M, Griffiths E, Wetzler M, Bullinger L, Cathers BE, Carr SA, Chopra R, Ebert BL | title = Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS | journal = Nature | volume = 523 | issue = 7559 | pages = 183–188 | date = July 2015 | pmid = 26131937 | pmc = 4853910 | doi = 10.1038/nature14610 | bibcode = 2015Natur.523..183K }} (see also thalidomide, pomalidomide, mezigdomide, iberdomide, avadomide)
• CC-90009 [CRBN-GSPT1] Induces GSPT1 degradation via CRBN recruitment.{{cite journal | vauthors = Hansen JD, Correa M, Alexander M, Nagy M, Huang D, Sapienza J, Lu G, LeBrun LA, Cathers BE, Zhang W, Tang Y, Ammirante M, Narla RK, Piccotti JR, Pourdehnad M, Lopez-Girona A | title = CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 4 | pages = 1835–1843 | date = February 2021 | pmid = 33591756 | doi = 10.1021/acs.jmedchem.0c01489 }}
• E7820/Indisulam [DCAF15-RBM39, RBM23] Recruit DCAF15 E3 ligase to degrade RBM39/RBM23.{{cite journal | vauthors = Faust TB, Yoon H, Nowak RP, Donovan KA, Li Z, Cai Q, Eleuteri NA, Zhang T, Gray NS, Fischer ES | title = Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15 | journal = Nature Chemical Biology | volume = 16 | issue = 1 | pages = 7–14 | date = January 2020 | pmid = 31686031 | pmc = 6917914 | doi = 10.1038/s41589-019-0378-3 }} [see also indisulam, tasisulam]
• CR8 [CDK12-DDB1] Links CDK12 to CRL4-DDB1 ligase, triggering CDK12-associated cyclin K degradation.{{cite journal | vauthors = Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL | title = The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K | journal = Nature | volume = 585 | issue = 7824 | pages = 293–297 | date = September 2020 | pmid = 32494016 | pmc = 7486275 | doi = 10.1038/s41586-020-2374-x }}
• PF-07208254 (BDK-BCKDH E2) Degrades branched-chain ketoacid dehydrogenase (BCKDH) via BDK recruitment (assumed degradative).{{cite journal | vauthors = Roth Flach RJ, Bollinger E, Reyes AR, Laforest B, Kormos BL, Liu S, Reese MR, Martinez Alsina LA, Buzon L, Zhang Y, Bechle B, Rosado A, Sahasrabudhe PV, Knafels J, Bhattacharya SK, Omoto K, Stansfield JC, Hurley LD, Song L, Luo L, Breitkopf SB, Monetti M, Cunio T, Tierney B, Geoly FJ, Delmore J, Siddall CP, Xue L, Yip KN, Kalgutkar AS, Miller RA, Zhang BB, Filipski KJ | title = Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels | journal = Nature Communications | volume = 14 | issue = 1 | pages = 4812 | date = August 2023 | pmid = 37558654 | pmc = 10412597 | doi = 10.1038/s41467-023-40536-y | bibcode = 2023NatCo..14.4812R }}
• SRI-41315 (eRF1-ribosome) Promotes eRF1-ribosome interactions to degrade translationally stalled proteins.{{cite journal | vauthors = Coelho JP, Yip MC, Oltion K, Taunton J, Shao S | title = The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center | journal = Nature Chemical Biology | volume = 20 | issue = 7 | pages = 877–884 | date = July 2024 | pmid = 38172604 | pmc = 11253071 | doi = 10.1038/s41589-023-01521-0 }}
• BI-3802 [(BCL6) Induces BCL6 polymerization and proteasomal degradation.{{cite journal | vauthors = Słabicki M, Yoon H, Koeppel J, Nitsch L, Roy Burman SS, Di Genua C, Donovan KA, Sperling AS, Hunkeler M, Tsai JM, Sharma R, Guirguis A, Zou C, Chudasama P, Gasser JA, Miller PG, Scholl C, Fröhling S, Nowak RP, Fischer ES, Ebert BL | title = Small-molecule-induced polymerization triggers degradation of BCL6 | journal = Nature | volume = 588 | issue = 7836 | pages = 164–168 | date = December 2020 | pmid = 33208943 | pmc = 7816212 | doi = 10.1038/s41586-020-2925-1 | bibcode = 2020Natur.588..164S }}
• AMPTX-1 (BRD9-DCAF16) Recruits DCAF16 E3 ligase to degrade BRD9.{{cite journal | vauthors = Hughes SJ, Stec WJ, Davies CT, McGarry D, Williams A, Del Barco Barrantes I, Harris R, Owens DD, Fawcett A, Hellicar J, Meier GP |title=Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept | journal = bioRxiv |date=2025-01-02 |url=https://www.biorxiv.org/content/10.1101/2024.12.31.630899v1.full |access-date=2025-01-03 |language=en |doi=10.1101/2024.12.31.630899 |url-access=subscription }}
• dGEM3 (V) HL-GEMIN3] Links GEMIN3 to VHL E3 ligase for degradation.{{cite journal | vauthors = Bushman JW, Deng W, Samarasinghe KT, Liu HY, Li S, Vaish A, Golkar A, Ou SC, Ahn J, Harijan RK, Han H |title=Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq | journal = bioRxiv |date=2025-03-19 |url=http://biorxiv.org/lookup/doi/10.1101/2025.03.19.644003 |access-date=2025-03-22 |language=en |doi=10.1101/2025.03.19.644003 }}
• NVP-DKY709 [CRBN-IKZF2]{{cite journal | vauthors = Bonazzi S, d'Hennezel E, Beckwith RE, Xu L, Fazal A, Magracheva A, Ramesh R, Cernijenko A, Antonakos B, Bhang HC, Caro RG, Cobb JS, Ornelas E, Ma X, Wartchow CA, Clifton MC, Forseth RR, Fortnam BH, Lu H, Csibi A, Tullai J, Carbonneau S, Thomsen NM, Larrow J, Chie-Leon B, Hainzl D, Gu Y, Lu D, Meyer MJ, Alexander D, Kinyamu-Akunda J, Sabatos-Peyton CA, Dales NA, Zécri FJ, Jain RK, Shulok J, Wang YK, Briner K, Porter JA, Tallarico JA, Engelman JA, Dranoff G, Bradner JE, Visser M, Solomon JM | title = Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy | journal = Cell Chemical Biology | volume = 30 | issue = 3 | pages = 235–247.e12 | date = March 2023 | pmid = 36863346 | doi = 10.1016/j.chembiol.2023.02.005 }} (see also PLX-4545){{Cite web |title=Discovery of PLX-4545, a molecular glue degrader of IKZF2 |url=https://acs.digitellinc.com/p/s/discovery-of-plx-4545-a-molecular-glue-degrader-of-ikzf2-605250 |access-date=2024-10-28 |website=acs.digitellinc.com |language=en}}
• DEG-35 [CRBN-IKZF2, CK1α]{{cite journal | vauthors = Park SM, Miyamoto DK, Han GY, Chan M, Curnutt NM, Tran NL, Velleca A, Kim JH, Schurer A, Chang K, Xu W, Kharas MG, Woo CM | title = Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells | journal = Cancer Cell | volume = 41 | issue = 4 | pages = 726–739.e11 | date = April 2023 | pmid = 36898380 | pmc = 10466730 | doi = 10.1016/j.ccell.2023.02.010 }}
• SJ3149 [CRBN-IKZF1, IKZF3, CK1α]{{cite journal | vauthors = Nishiguchi G, Mascibroda LG, Young SM, Caine EA, Abdelhamed S, Kooijman JJ, Miller DJ, Das S, McGowan K, Mayasundari A, Shi Z, Barajas JM, Hiltenbrand R, Aggarwal A, Chang Y, Mishra V, Narina S, Thomas M, Loughran AJ, Kalathur R, Yu K, Zhou S, Wang X, High AA, Peng J, Pruett-Miller SM, Daniels DL, Urh M, Shelat AA, Mullighan CG, Riching KM, Zaman GJ, Fischer M, Klco JM, Rankovic Z | title = Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines | journal = Nature Communications | volume = 15 | issue = 1 | pages = 482 | date = January 2024 | pmid = 38228616 | pmc = 10791743 | doi = 10.1038/s41467-024-44698-1 | bibcode = 2024NatCo..15..482N }}
• dWIZ [CRBN-WIZ]{{cite journal | vauthors = Ting PY, Borikar S, Kerrigan JR, Thomsen NM, Aghania E, Hinman AE, Reyes A, Pizzato N, Fodor BD, Wu F, Belew MS, Mao X, Wang J, Chitnis S, Niu W, Hachey A, Cobb JS, Savage NA, Burke A, Paulk J, Dovala D, Lin J, Clifton MC, Ornelas E, Ma X, Ware NF, Sanchez CC, Taraszka J, Terranova R, Knehr J, Altorfer M, Barnes SW, Beckwith RE, Solomon JM, Dales NA, Patterson AW, Wagner J, Bouwmeester T, Dranoff G, Stevenson SC, Bradner JE | title = A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction | journal = Science | volume = 385 | issue = 6704 | pages = 91–99 | date = July 2024 | pmid = 38963839 | doi = 10.1126/science.adk6129 | bibcode = 2024Sci...385...91T }}
• SP-3164 [CRBN-IKZF3] (see also DRX-164){{cite journal | vauthors = DeWitt S, Czarnik AW, Jacques V | title = Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates | journal = ACS Medicinal Chemistry Letters | volume = 11 | issue = 10 | pages = 1789–1792 | date = October 2020 | pmid = 33062153 | pmc = 7549104 | doi = 10.1021/acsmedchemlett.0c00052 }}{{cite journal | vauthors = Jacques V, Czarnik AW, Judge TM, Van der Ploeg LH, DeWitt SH | title = Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 12 | pages = E1471–E1479 | date = March 2015 | pmid = 25775521 | pmc = 4378388 | doi = 10.1073/pnas.1417832112 | doi-access = free | bibcode = 2015PNAS..112E1471J }}

The concept of "molecular glue" originated in the late 20th century, with immunosuppressants like cyclosporine A (CsA) and FK506 identified as pioneering examples.{{Cite web |title=Molecular Glues: A New Dawn After PROTAC {{!}} Biopharma PEG |url=https://www.biochempeg.com/article/271.html |access-date=2023-11-14 |website=www.biochempeg.com}} CsA, discovered in 1971 during routine screening for antifungal antibiotics, exhibited immunosuppressive properties by inhibiting the peptidyl–prolyl isomerase activity of cyclophilin, ultimately preventing organ transplant rejections.{{cite journal | vauthors = Schreiber SL | title = The Rise of Molecular Glues | journal = Cell | volume = 184 | issue = 1 | pages = 3–9 | date = January 2021 | pmid = 33417864 | doi = 10.1016/j.cell.2020.12.020 | doi-access = free }} By 1979, CsA was used clinically, and FK506 (tacrolimus), discovered in 1987 by Fujisawa, emerged as a more potent immunosuppressant. The ensuing 4-year race to understand CsA and FK506's mechanisms led to the identification of FKBP12 as a common binding partner, marking the birth of the "molecular glue" concept. The term molecular glue found its way into publications in 1992, highlighting the selective gluing of specific proteins by antigenic peptides, akin to immunosuppressants acting as docking assemblies. The term, however, remained esoteric and hidden from keyword searches.

In the early 1990s, researchers delved into understanding the role of proximity in biological processes. The creation of synthetic "chemical inducers of proximity" (CIPs), such as FK1012, opened the door to more complex molecular glues. Rimiducid, a purposefully synthesized molecular glue, demonstrated its effectiveness in eliminating graft-versus-host disease by inducing dimerization of death-receptor fusion targets.

The exploration of molecular glues took a significant turn in 1996 with the discovery that discodermolide stabilized the association of alpha and beta tubulin monomers, functioning as a "molecular clamp" rather than inducing neo-associations. In 2000, the revelation that a synthetic compound, synstab-A, could induce associations of native proteins marked a shift towards the discovery of non-natural molecular glues.

In 2001, Kathleen Sakamoto, Craig M. Crews and Raymond J. Deshaies raised the concept of PROTACs, which consist of a heterobifunctional molecule with a ligand of an E3 ubiquitin ligase linked to a ligand of a target protein.{{cite journal | vauthors = Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ | title = Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 15 | pages = 8554–8559 | date = July 2001 | pmid = 11438690 | pmc = 37474 | doi = 10.1073/pnas.141230798 | doi-access = free | bibcode = 2001PNAS...98.8554S }} PROTACs are synthetic CIPs acting as protein degraders.

In 2007, the term “molecular glue” became popularized after it was independently coined by Ning Zheng to describe the mechanism of action of auxin, a class of plant hormones regulating many aspects of plant growth and development. By promoting the interaction between a plant E3 ubiquitin ligase, TIR1, and its substrate proteins, auxin induces the degradation of a family of transcriptional repressors.{{cite journal | vauthors = Gray WM, del Pozo JC, Walker L, Hobbie L, Risseeuw E, Banks T, Crosby WL, Yang M, Ma H, Estelle M | title = Identification of an SCF ubiquitin-ligase complex required for auxin response in Arabidopsis thaliana | journal = Genes & Development | volume = 13 | issue = 13 | pages = 1678–1691 | date = July 1999 | pmid = 10398681 | doi = 10.1101/gad.13.13.1678 | pmc = 316846 }} Auxin is chemically known as indole-3-acetic acid and has a molecular weight of 175 dalton. Unlike PROTACs and immunosuppressants such as CsA and FK506, auxin is a chemically simple and monovalent compound with drug-like properties obeying Lipinski’s rule of five. With no detectable affinity to the polyubiquitination substrate proteins of TIR1, auxin leverages the intrinsic weak affinity between the E3 ligase and its substrate proteins to enable stable protein complex formation. The same mechanism of action is shared by jasmonate, another plant hormone involved in wound and stress responses.{{cite journal | vauthors = Sheard LB, Tan X, Mao H, Withers J, Ben-Nissan G, Hinds TR, Kobayashi Y, Hsu FF, Sharon M, Browse J, He SY, Rizo J, Howe GA, Zheng N | title = Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor | journal = Nature | volume = 468 | issue = 7322 | pages = 400–405 | date = November 2010 | pmid = 20927106 | pmc = 2988090 | doi = 10.1038/nature09430 | bibcode = 2010Natur.468..400S }} The term “molecular glue” has since been used, particularly in the context of targeted protein degradation, to specifically describe monovalent compounds with drug-like properties capable of promoting productive protein-protein interactions, instead of CIPs in general.

In 2013, the mechanism of thalidomide analogs as molecular glue degraders had been revealed. Notably, thalidomide, discovered as a CRBN ligand in 2010, and lenalidomide enhance the binding of CK1α to the E3 ubiquitin ligase, solidifying their role as molecular glues. Subsequently, indisulam was identified as a molecular glue capable of degrading RBM39 by targeting DCAF15 in 2017. These compounds are considered molecular glues because of their monovalency and chemical simplicity, which are consistent with the definition proposed by Shiyun Cao and Ning Zheng.{{cite journal | vauthors = Cao S, Kang S, Mao H, Yao J, Gu L, Zheng N | title = Defining molecular glues with a dual-nanobody cannabidiol sensor | journal = Nature Communications | volume = 13 | issue = 1 | pages = 815 | date = February 2022 | pmid = 35145136 | pmc = 8831599 | doi = 10.1038/s41467-022-28507-1 | bibcode = 2022NatCo..13..815C }} Analogous to auxin, these compounds are distinct from PROTACs, displaying no detectable affinity to the substrate proteins of the E3 ubiquitin ligases.

The year 2020 saw the discovery of autophagic molecular degraders and the identification of BI-3802 as a molecular glue inducing the polymerization and degradation of BCL6. Additionally, chemogenomic screening revealed structurally diverse molecular glue degraders targeting cyclin K. The discovery that manumycin polyketides acted as molecular glues, fostering interactions between UBR7 and P53, further expanded the understanding of molecular glue functions.

In recent years, the field of molecular glues has witnessed an explosion of discoveries targeting native proteins. Examples include synthetic FKBP12-binding glues like FKBP12-rapadocin, which targets the adenosine transporter SLC29A1. Thalidomide and lenalidomide, classified as immunomodulatory drugs (IMiDs), were identified as small-molecule glues inducing ubiquitination of transcription factors via E3 ligase complexes. Computational searches for molecular-glue degraders since 2020 have added novel probes to the ever-expanding landscape of molecular glues.{{cite journal | vauthors = Dudas B, Athanasiou C, Mobarec JC, Rosta E | title = Quantifying Cooperativity Through Binding Free Energies in Molecular Glue Degraders | journal = ChemRxiv | date = October 2024 | doi = 10.26434/chemrxiv-2024-920w5 }} Furthermore, computational methods are starting to shed light onto molecular glues mechanisms of action.

The transformative power of molecular glues in medicine became evident as drugs like sandimmune, tacrolimus, sirolimus, thalidomide, lenalidomide, and taxotere proved effective. The concept of inducing protein associations has shown promise in gene therapy and has become a potent tool in understanding cell circuitry. As the field continues to advance, the discovery of new molecular glues offers the potential to reshape drug discovery and overcome previously labeled "undruggable" targets. The future of molecular glues holds promise for rewiring cellular circuitry and providing innovative solutions in precision medicine.

While molecular glue compounds hold great potential in various fields, there are challenges to overcome. Ensuring the specificity of these compounds and minimizing off-target effects is essential. Additionally, understanding the long-term consequences of manipulating protein interactions is crucial for their safe and effective application in medicine.

Ongoing research in molecular glue is unlocking new compounds and insights into their mechanisms. With an expanding understanding of protein-protein interactions, molecular glue holds significant promise across biology, medicine, and chemistry, potentially revolutionizing cellular processes and advancing innovative disease treatments. As this field progresses, it may open new therapeutic avenues and deepen our understanding of life's molecular intricacies.

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Category:Medicinal chemistry

Category:Biotechnology