Saridegib

• CAT Number: I009210
• CAS Number: 1037210-93-7
• Molecular Formula: C29H48N2O3S
• Molecular Weight: 504.774
• Purity: ≥95%
• Solubility: Soluble in DMSO
• Storage: 0 - 4 °C for short term, or -20 °C for long term
• IUPAC Name: N-[(3R,3/'R,3/'aS,4aR,6/'S,6aR,6bS,7/'aR,9S,12aS,12bS)-3/',6/',11,12b-tetramethylspiro[1,2,3,4,4a,5,6,6a,6b,7,8,10,12,12a-tetradecahydronaphtho[2,1-a]azulene-9,2/'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-yl]methanesulfonamide
• InChI: InChI=1S/C29H48N2O3S/c1-17-12-26-27(30-16-17)19(3)29(34-26)11-9-22-23-7-6-20-13-21(31-35(5,32)33)8-10-28(20,4)25(23)14-24(22)18(2)15-29/h17,19-23,25-27,30-31H,6-16H2,1-5H3/t17-,19+,20+,21+,22-,23-,25-,26+,27-,28-,29-/m0/s1
• InChIKey: HZLFFNCLTRVYJG-WWGOJCOQSA-N
• SMILES: CC1CC2C(C(C3(O2)CCC4C5CCC6CC(CCC6(C5CC4=C(C3)C)C)NS(=O)(=O)C)C)NC1

Saridegib, also known as IPI-926, is an orally bioavailable, cyclopamine-derived (for structure comparison see Fig 1) inhibitor of the Hedgehog (Hh) pathway with potential antineoplastic activity. Specifically, Hedgehog pathway inhibitor IPI-926 binds to and inhibits the cell membrane-spanning G-protein coupled receptor SMO, which may result in the suppression of Hh pathway signaling and a decrease in tumor cell proliferation and survival. SMO is activated upon binding of Hh ligand to the cell surface receptor Patched (PTCH); inappropriate activation of Hh signaling and uncontrolled cellular proliferation may be associated with SMO mutations.

Reference

1:Proc Natl Acad Sci U S A. 2012 May 15;109(20):7859-64. doi: 10.1073/pnas.1114718109. Epub 2012 May 1. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.Lee MJ,Hatton BA,Villavicencio EH,Khanna PC,Friedman SD,Ditzler S,Pullar B,Robison K,White KF,Tunkey C,LeBlanc M,Randolph-Habecker J,Knoblaugh SE,Hansen S,Richards A,Wainwright BJ,McGovern K,Olson JM, PMID: 22550175 PMCID: PMC3356655 DOI: 10.1073/pnas.1114718109 Abstract: The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.