Saridegib

Saridegib

Names
IUPAC name N-((2S,3R,3aS,3′R,4a′R,6S,6a′R,6b′S,7aR,12a&prmie;S,12b′S)-3,6,11′,12b′-tetramethyl-2′,3a,3′,4,4′,4a′,5,5&prmie;,6,6′,6a′,6b′,7,7a,7′,8′,10′,12′,12a′,12b′-icosahydro-1′H,3H-spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,1-a]azulen]-3'-yl)methanesulfonamide
Other names saridegib
Identifiers
CAS Number	1037210-93-7
3D model (Jmol)	Interactive image
ChEMBL	ChEMBL538867
ChemSpider	26353073
IUPHAR/BPS	8198
PubChem	25027363
UNII	JT96FPU35X
SMILES [H][C@]12[C@@]([C@@]3([H])C(C2)=C(C)C[C@@]4(O[C@@](C[C@H](C)CN5)([H])[C@]5([H])[C@H]4C)CC3)([H])CC[C@]6([H])C[C@H](NS(C)(=O)=O)CC[C@@]61C
Properties
Chemical formula	C29H48N2O3S
Molar mass	504.77 g·mol^−1
Pharmacology
Routes of administration	Oral
Legal status	Investigational
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Saridegib, also known as IPI-926, is an experimental drug candidate undergoing clinical trials for the treatment of various types of cancer, including hard-to-treat hematologic malignancies such as myelofibrosis and ligand-dependent tumors such as chondrosarcoma.^[1] IPI-926 exhibits its pharmacological effect by inhibition of the G protein-coupled receptor smoothened, a component of the hedgehog signaling pathway.^[2] Chemically, it is a semi-synthetic derivative of the alkaloid cyclopamine. The process begins with cyclopamine extracted from harvested Veratrum californicum which is taken through a series of alterations resulting in an analogue of the natural product cyclopamine, making IPI-926 the only compound in development/testing that is not fully synthetic.^[2]

Drug class

Saridegib is a member of a class of anti-cancer compounds known as hedgehog inhibitors (Hhi). Most of these compounds affect the hedgehog signaling pathway via inhibition of smoothened (Smo), a key component of the pathway. Depending on when a Hh inhibiting compound is approved by the U.S. Food and Drug Administration (FDA), there may be a perceived need for one to be differentiated over another for marketing purposes, which could lead to different nomenclature (e.g., a Hhi or an agonist of Smo). This marketing technique is more of a differentiation strategy than a scientific property of these compounds, as the mechanism of action (MOA) in the end is inhibition of the Hh pathway, targeting cancer stem cells. However, as these new compounds are further studied, identification of differences in a compound's MOA, could lead to hypotheses regarding the stage at which Smo is inhibited, where along the pathway the compound binds, or specific binding properties of a compound. If these hypotheses are proven, claims could be made regarding a specific compound's MOA and how it affects efficacy, safety, combinability with other cancer treatments, etc. Scientific data in support of such hypotheses have not been published to date.

There are currently no drugs in the Hhi class FDA approved, however IPI-926 and GDC-0449 are the 2 leading compounds in the class. IPI-926, GDC-0449, and LDE-225 are the only compounds that have generic names passed by the United States Adopted Name (USAN) council (Infinity IPI-926/saridegib, Genentech GDC-0449/vismodegib, and Novartis LDE-225/erismodegib). Although Infinity is further along in chondrosarcoma, myelofibrosis, and AML, Roche/Genentech recently submitted an NDA for GDC-0449 for the treatment of adults with advanced basal cell carcinoma (BCC) when surgery is no longer an option, and the FDA has accepted and has filed the NDA, giving it priority review status. Thus it appears that Roche/Genentech will be the first Hhi to market with GDC-0449, if approved, for the treatment of advanced BCC, with Infinity second to market with IPI-926 for treatment in chondrosarcoma. It appears Infinity will not pursue an indication for BCC and focus on cancers with high unmet needs.^{[1][3][4][5][6]}

Other Hhi-class compounds not as far along in development as IPI-926 and GDC-0449 include:^[7]

• Novartis' LDE-225 (USAN generic name erismodegib)
• Exelixis/Bristol-Myers Squibb's BMS-833923 (XL139)
• Millennium Pharmaceuticals's TAK-441
• Pfizer's PF-04449913

References

1. "Pipeline: IPI-926". Infinity Pharmaceuticals.
2. Tremblay, MR; Lescarbeau, A; Grogan, MJ; Tan, E; Lin, G; Austad, BC; Yu, LC; Behnke, ML; et al. (2009). "Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926)". Journal of Medicinal Chemistry. 52 (14): 4400–18. doi:10.1021/jm900305z. PMID 19522463.
3. "Pipeline". Infinity Pharmaceuticals.
4. "Genentech Pipeline". Genentech.
5. "USAN Stem List" (PDF). AMA.
6. "Names under consideration". AMA.
7. "Search results for Hh clinical trials". United National Institute of Health's ClinicalTrials.gov.