:Smoothened agonist
{{Short description|Chemical compound}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| IUPAC_name = 3-chloro-N-[(1r,4r)-4-(methylamino)cyclohexyl]-N-[3-(pyridin-4-yl)benzyl]benzo[b]thiophene-2-carboxamide
| image = Chemical_structural_formula_of_smoothened_agonist.png
| width = 250
| tradename =
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 912545-86-9
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4XN97SZK4J
| CAS_supplemental =
364590-63-6 (hydrochloride)
| ATC_prefix =
| ATC_suffix =
| PubChem = 5284330
| ChEBI = 138438
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21541484
| C=28 | H=28 | Cl=1 | N=3 | O=1 | S=1
| smiles = ClC1=C(C(N([C@H]2CC[C@H](NC)CC2)CC3=CC=CC(C4=CC=NC=C4)=C3)=O)SC5=CC=CC=C51
| StdInChI = 1S/C28H28ClN3OS/c1-30-22-9-11-23(12-10-22)32(28(33)27-26(29)24-7-2-3-8-25(24)34-27)18-19-5-4-6-21(17-19)20-13-15-31-16-14-20/h2-8,13-17,22-23,30H,9-12,18H2,1H3/t22-,23-
| StdInChIKey = VFSUUTYAEQOIMW-YHBQERECSA-N
}}
Smoothened agonist (SAG) was one of the first small-molecule agonists developed for the protein Smoothened,{{cite journal |vauthors=Lewis C, Krieg PA | title = Reagents for developmental regulation of Hedgehog signaling | journal = Methods | volume = 66| pages = 390–397|date=August 2013 | issue = 3 | pmid = 23981360 | doi = 10.1016/j.ymeth.2013.08.022 }} a key part of the hedgehog signaling pathway, which is involved in brain development as well as having a number of other functions in the body.
Smoothened agonist has been shown to aid proliferation and survival of developing neurons,{{cite journal |vauthors=Bragina O, Sergejeva S, Serg M, Zarkovsky T, Maloverjan A, Kogerman P, Zarkovsky A | title = Smoothened agonist augments proliferation and survival of neural cells | journal = Neurosci. Lett. | volume = 482 | issue = 2 | pages = 81–5 |date=September 2010 | pmid = 20600593 | doi = 10.1016/j.neulet.2010.06.068 | s2cid = 24186568 }} and prevent drug-induced brain injury.{{cite journal |vauthors=Heine VM, Griveau A, Chapin C, Ballard PL, Chen JK, Rowitch DH | title = A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury | journal = Sci Transl Med | volume = 3 | issue = 105 | pages = 105ra104 |date=October 2011 | pmid = 22013124 | pmc = 3694585 | doi = 10.1126/scitranslmed.3002731 }} When injected into the cerebellum of newborn mice with an induced Down syndrome-like condition, Smoothened agonist was able to stimulate normal cerebellum development, resulting in significant behavioural improvement once the mice had grown to adulthood.{{cite journal |vauthors=Das I, Park JM, Shin JH, Jeon SK, Lorenzi H, Linden DJ, Worley PF, Reeves RH | title = Hedgehog agonist therapy corrects structural and cognitive deficits in a down syndrome mouse model | journal = Sci Transl Med | volume = 5 | issue = 201 | pages = 201ra120 |date=September 2013 | pmid = 24005160 | doi = 10.1126/scitranslmed.3005983 | pmc=4006719}}
Smoothened Agonist was capable of inducing androgen production in both prostate and bone stromal cells that was significantly greater than even similarly treated prostate cancer cells.{{cite journal| vauthors=Lubik AA, Nouri M, Truong S, Ghaffari M, Adomat HH, Corey E, Cox ME, Li N, Guns ES, Yenki P, Pham S, Buttyan R | title=Paracrine Sonic Hedgehog Signaling Contributes Significantly to Acquired Steroidogenesis in the Prostate Tumor Microenvironment|journal=International Journal of Cancer|date=2016| volume=140| issue=2| pages=358–369|pmid=27672740|doi=10.1002/ijc.30450| s2cid=2354209| doi-access=free}}
The substance has been used as part of a chemical cocktail to turn old and senescent human cells back into young ones (as measured by transcriptomic age), without turning them all the way back into undifferentiated stem cells.{{cite journal | vauthors = Yang JH, Petty CA, Dixon-McDougall T, Lopez MV, Tyshkovskiy A, Maybury-Lewis S, Tian X, Ibrahim N, Chen Z, Griffin PT, Arnold M, Li J, Martinez OA, Behn A, Rogers-Hammond R, Angeli S, Gladyshev VN, Sinclair DA | title = Chemically induced reprogramming to reverse cellular aging | journal = Aging | volume = 15 | issue = 13 | pages = 5966–5989 | date = July 2023 | pmid = 37437248 | pmc = 10373966 | doi = 10.18632/aging.204896 }}