Smoothened agonist

Smoothened agonist
Identifiers
	IUPAC name 3-chloro-N-[(1r,4r)-4-(methylamino)cyclohexyl]-N-[3-(pyridin-4-yl)benzyl]benzo[b]thiophene-2-carboxamide;
CAS Number	912545-86-9 ; 364590-63-6 (hydrochloride);
PubChem CID	5284330;
ChemSpider	21541484 ;
UNII	4XN97SZK4J;
ChEBI	CHEBI:138438;
CompTox Dashboard (EPA)	DTXSID80415294 ;
Chemical and physical data
Formula	C28H28ClN3OS
Molar mass	490.06 g·mol−1
3D model (JSmol)	Interactive image;
	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;
	InChI InChI=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-; Key:VFSUUTYAEQOIMW-YHBQERECSA-N;

Smoothened agonist (SAG) was one of the first small-molecule agonists developed for the protein Smoothened,^[1] 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,^[2] and prevent drug-induced brain injury.^[3] 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.^[4]

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.^[5]

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.^[6]

References

^ Lewis C, Krieg PA (August 2013). "Reagents for developmental regulation of Hedgehog signaling". Methods. 66 (3): 390–397. doi:10.1016/j.ymeth.2013.08.022. PMID 23981360.
^ Bragina O, Sergejeva S, Serg M, Zarkovsky T, Maloverjan A, Kogerman P, et al. (September 2010). "Smoothened agonist augments proliferation and survival of neural cells". Neurosci. Lett. 482 (2): 81–5. doi:10.1016/j.neulet.2010.06.068. PMID 20600593. S2CID 24186568.
^ Heine VM, Griveau A, Chapin C, Ballard PL, Chen JK, Rowitch DH (October 2011). "A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury". Sci Transl Med. 3 (105): 105ra104. doi:10.1126/scitranslmed.3002731. PMC 3694585. PMID 22013124.
^ Das I, Park JM, Shin JH, Jeon SK, Lorenzi H, Linden DJ, et al. (September 2013). "Hedgehog agonist therapy corrects structural and cognitive deficits in a down syndrome mouse model". Sci Transl Med. 5 (201): 201ra120. doi:10.1126/scitranslmed.3005983. PMC 4006719. PMID 24005160.
^ Lubik AA, Nouri M, Truong S, Ghaffari M, Adomat HH, Corey E, et al. (2016). "Paracrine Sonic Hedgehog Signaling Contributes Significantly to Acquired Steroidogenesis in the Prostate Tumor Microenvironment". International Journal of Cancer. 140 (2): 358–369. doi:10.1002/ijc.30450. PMID 27672740. S2CID 2354209.
^ Yang JH, Petty CA, Dixon-McDougall T, Lopez MV, Tyshkovskiy A, Maybury-Lewis S, et al. (July 2023). "Chemically induced reprogramming to reverse cellular aging". Aging. 15 (13): 5966–5989. doi:10.18632/aging.204896. PMC 10373966. PMID 37437248.

[pmid23981360-1] Lewis C, Krieg PA (August 2013). "Reagents for developmental regulation of Hedgehog signaling". Methods. 66 (3): 390–397. doi:10.1016/j.ymeth.2013.08.022. PMID 23981360.

[pmid20600593-2] Bragina O, Sergejeva S, Serg M, Zarkovsky T, Maloverjan A, Kogerman P, et al. (September 2010). "Smoothened agonist augments proliferation and survival of neural cells". Neurosci. Lett. 482 (2): 81–5. doi:10.1016/j.neulet.2010.06.068. PMID 20600593. S2CID 24186568.

[pmid22013124-3] Heine VM, Griveau A, Chapin C, Ballard PL, Chen JK, Rowitch DH (October 2011). "A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury". Sci Transl Med. 3 (105): 105ra104. doi:10.1126/scitranslmed.3002731. PMC 3694585. PMID 22013124.

[pmid24005160-4] Das I, Park JM, Shin JH, Jeon SK, Lorenzi H, Linden DJ, et al. (September 2013). "Hedgehog agonist therapy corrects structural and cognitive deficits in a down syndrome mouse model". Sci Transl Med. 5 (201): 201ra120. doi:10.1126/scitranslmed.3005983. PMC 4006719. PMID 24005160.

[5] Lubik AA, Nouri M, Truong S, Ghaffari M, Adomat HH, Corey E, et al. (2016). "Paracrine Sonic Hedgehog Signaling Contributes Significantly to Acquired Steroidogenesis in the Prostate Tumor Microenvironment". International Journal of Cancer. 140 (2): 358–369. doi:10.1002/ijc.30450. PMID 27672740. S2CID 2354209.

[6] Yang JH, Petty CA, Dixon-McDougall T, Lopez MV, Tyshkovskiy A, Maybury-Lewis S, et al. (July 2023). "Chemically induced reprogramming to reverse cellular aging". Aging. 15 (13): 5966–5989. doi:10.18632/aging.204896. PMC 10373966. PMID 37437248.

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