JQ1

Interest in JQ1 as a cancer therapeutic stemmed from its ability to inhibit BRD4 and BRD3, both of which form fusion oncogenes that drive NUT midline carcinoma.{{cite journal | vauthors = Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE | title = Selective inhibition of BET bromodomains | journal = Nature | volume = 468 | issue = 7327 | pages = 1067–73 | date = December 2010 | pmid = 20871596 | pmc = 3010259 | doi = 10.1038/nature09504 | bibcode = 2010Natur.468.1067F }}{{cite journal | vauthors = Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, West NH, Agoston ES, Reynoird N, Khochbin S, Ince TA, Christie A, Janeway KA, Vargas SO, Perez-Atayde AR, Aster JC, Sallan SE, Kung AL, Bradner JE, French CA | title = Differentiation of NUT midline carcinoma by epigenomic reprogramming | journal = Cancer Research | volume = 71 | issue = 7 | pages = 2686–96 | date = April 2011 | pmid = 21447744 | pmc = 3070805 | doi = 10.1158/0008-5472.CAN-10-3513 }} Subsequent work demonstrated that a number of cancers including some forms of acute myelogenous leukemia (AML), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL) were also highly sensitive to BET inhibitors.{{cite journal | vauthors = Belkina AC, Denis GV | title = BET domain co-regulators in obesity, inflammation and cancer | journal = Nature Reviews. Cancer | volume = 12 | issue = 7 | pages = 465–77 | date = June 2012 | pmid = 22722403 | pmc = 3934568 | doi = 10.1038/nrc3256 }}{{cite journal | vauthors = Shi J, Vakoc CR | title = The mechanisms behind the therapeutic activity of BET bromodomain inhibition | journal = Molecular Cell | volume = 54 | issue = 5 | pages = 728–36 | date = June 2014 | pmid = 24905006 | pmc = 4236231 | doi = 10.1016/j.molcel.2014.05.016 }}{{cite journal | vauthors = Da Costa D, Agathanggelou A, Perry T, Weston V, Petermann E, Zlatanou A, Oldreive C, Wei W, Stewart G, Longman J, Smith E, Kearns P, Knapp S, Stankovic T | title = BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia | journal = Blood Cancer Journal | volume = 3 | issue = 7 | pages = e126 | date = July 2013 | pmid = 23872705 | pmc = 3730202 | doi = 10.1038/bcj.2013.24 }}

JQ1 has also been investigated for other applications in the treatment of HIV infection,{{cite journal | vauthors = Banerjee C, Archin N, Michaels D, Belkina AC, Denis GV, Bradner J, Sebastiani P, Margolis DM, Montano M | title = BET bromodomain inhibition as a novel strategy for reactivation of HIV-1 | journal = Journal of Leukocyte Biology | volume = 92 | issue = 6 | pages = 1147–54 | date = December 2012 | pmid = 22802445 | pmc = 3501896 | doi = 10.1189/jlb.0312165 }} as a male contraceptive,{{cite journal | vauthors = Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE | title = Small-molecule inhibition of BRDT for male contraception | journal = Cell | volume = 150 | issue = 4 | pages = 673–84 | date = August 2012 | pmid = 22901802 | pmc = 3420011 | doi = 10.1016/j.cell.2012.06.045 }} and in slowing the progression of heart disease.{{cite journal | vauthors = Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM | title = BET bromodomains mediate transcriptional pause release in heart failure | journal = Cell | volume = 154 | issue = 3 | pages = 569–82 | date = August 2013 | pmid = 23911322 | pmc = 4090947 | doi = 10.1016/j.cell.2013.07.013 }}

JQ1 has been functionalized in numerous different studies of targeted protein degradation. For example, conjugation of JQ1 to phthalimide moieties such as that found in thalidomide recruits the E3 ubiquitin ligase cereblon (CRBN) to effect proteasomal degradation of BRD4.{{cite journal | vauthors = Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE | title = DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation | journal = Science | volume = 348 | issue = 6241 | pages = 1376–1381 | date = June 2015 | pmid = 25999370 | pmc = 4937790 | doi = 10.1126/science.aab1433 }} Monovalent degraders based on functionalizing JQ1 have also been discovered.{{Cite journal | vauthors = Blake RA |date=2019-07-01 |title=Abstract 4452: GNE-0011, a novel monovalent BRD4 degrader |url=https://aacrjournals.org/cancerres/article/79/13_Supplement/4452/636335/Abstract-4452-GNE-0011-a-novel-monovalent-BRD4 |journal=Cancer Research |language=en |volume=79 |issue=13_Supplement |pages=4452 |doi=10.1158/1538-7445.AM2019-4452 |issn=0008-5472}}{{cite journal | vauthors = Hsia O, Hinterndorfer M, Cowan AD, Iso K, Ishida T, Sundaramoorthy R, Nakasone MA, Imrichova H, Schätz C, Rukavina A, Husnjak K, Wegner M, Correa-Sáez A, Craigon C, Casement R, Maniaci C, Testa A, Kaulich M, Dikic I, Winter GE, Ciulli A | title = Targeted protein degradation via intramolecular bivalent glues | journal = Nature | volume = 627 | issue = 8002 | pages = 204–211 | date = March 2024 | pmid = 38383787 | pmc = 10917667 | doi = 10.1038/s41586-024-07089-6 }}{{cite journal | vauthors = Lim M, Cong TD, Orr LM, Toriki ES, Kile AC, Papatzimas JW, Lee E, Lin Y, Nomura DK | title = DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders | journal = ACS Central Science | volume = 10 | issue = 7 | pages = 1318–1331 | date = July 2024 | pmid = 39071058 | pmc = 11273451 | doi = 10.1021/acscentsci.4c00286 }}{{cite journal | vauthors = Shergalis AG, Marin VL, Rhee DY, Senaweera S, McCloud RL, Ronau JA, Hutchins CW, McLoughlin S, Woller KR, Warder SE, Vasudevan A, Reitsma JM | title = CRISPR Screen Reveals BRD2/4 Molecular Glue-like Degrader via Recruitment of DCAF16 | journal = ACS Chemical Biology | volume = 18 | issue = 2 | pages = 331–339 | date = February 2023 | pmid = 36656921 | doi = 10.1021/acschembio.2c00747 }}

Fusion of JQ1 to other molecules targeting specific genomic loci has been demonstrated to rewire transcription.{{cite journal | vauthors = Erwin GS, Grieshop MP, Ali A, Qi J, Lawlor M, Kumar D, Ahmad I, McNally A, Teider N, Worringer K, Sivasankaran R, Syed DN, Eguchi A, Ashraf M, Jeffery J, Xu M, Park PM, Mukhtar H, Srivastava AK, Faruq M, Bradner JE, Ansari AZ | title = Synthetic transcription elongation factors license transcription across repressive chromatin | journal = Science | volume = 358 | issue = 6370 | pages = 1617–1622 | date = December 2017 | pmid = 29192133 | pmc = 6037176 | doi = 10.1126/science.aan6414 }}{{cite journal | vauthors = Gourisankar S, Krokhotin A, Ji W, Liu X, Chang CY, Kim SH, Li Z, Wenderski W, Simanauskaite JM, Yang H, Vogel H, Zhang T, Green MR, Gray NS, Crabtree GR | title = Rewiring cancer drivers to activate apoptosis | journal = Nature | volume = 620 | issue = 7973 | pages = 417–425 | date = August 2023 | pmid = 37495688 | pmc = 10749586 | doi = 10.1038/s41586-023-06348-2 }}

• Male contraceptive
• CDD-2807
• TDI-11861
• YCT529

{{Reflist|32em}}

Category:Contraception for males

Category:Experimental cancer drugs

Category:Thienotriazolodiazepines

Category:Tert-butyl compounds