GDC-0917

• CAT Number: I001716
• CAS Number: 1446182-94-0
• Molecular Formula: C₂₉H₃₆N₆O₄S
• Molecular Weight: 564.7
• Purity: ≥95%
• Target: IAPs inhibitor
• Solubility: DMSO: ≥ 61 mg/mL
• Storage: Store at -20C
• InChI: InChI=1S/C29H36N6O4S/c1-18(30-2)24(36)32-23(20-12-7-4-8-13-20)29(38)35-16-9-14-21(35)25(37)34-27-22(19-10-5-3-6-11-19)33-28(40-27)26-31-15-17-39-26/h3,5-6,10-11,15,17-18,20-21,23,30H,4,7-9,12-14,16H2,1-2H3,(H,32,36)(H,34,37)/t18-,21?,23-/m0/s1
• InChIKey: HSHPBORBOJIXSQ-IAZWUMQMSA-N
• SMILES: CC(C(=O)NC(C1CCCCC1)C(=O)N2CCCC2C(=O)NC3=C(N=C(S3)C4=NC=CO4)C5=CC=CC=C5)NC

GDC-0917 (CAT: I001716) is an orally bioavailable small-molecule inhibitor of the inhibitor of apoptosis proteins (IAPs), including XIAP (X-linked inhibitor of apoptosis protein), cIAP1 (cellular inhibitor of apoptosis protein 1), and cIAP2 (cellular inhibitor of apoptosis protein 2). By inhibiting these proteins, GDC-0917 promotes apoptosis (programmed cell death) and has the potential to sensitize cancer cells to chemotherapy. It has shown efficacy in preclinical models of various cancers, including hematologic malignancies and solid tumors. GDC-0917 is being investigated in clinical trials for the treatment of advanced or refractory solid tumors and lymphomas.

Reference

1:Clin Cancer Res. 2016 Sep 15;22(18):4567-73. doi: 10.1158/1078-0432.CCR-16-0308. Epub 2016 Apr 13. A Phase I Dose-Escalation Study Evaluating the Safety Tolerability and Pharmacokinetics of CUDC-427, a Potent, Oral, Monovalent IAP Antagonist, in Patients with Refractory Solid Tumors.Tolcher AW,Bendell JC,Papadopoulos KP,Burris HA,Patnaik A,Fairbrother WJ,Wong H,Budha N,Darbonne WC,Peale F,Mamounas M,Royer-Joo S,Yu R,Portera CC,Infante JR, PMID: 27076626 DOI: 10.1158/1078-0432.CCR-16-0308 Abstract: PURPOSE: To determine the dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins.EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily 14-day on/7-day off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMC), and monocyte chemoattractant protein-1 (MCP-1) levels.RESULTS: Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1, and 5 patients experienced AEs related to CUDC-427 that led to discontinuation and included grade 3 pruritus, and fatigue, and grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg orally daily for 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses in one patient with ovarian cancer and one patient with MALT lymphoma.CONCLUSIONS: CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies. Clin Cancer Res; 22(18); 4567-73. ©2016 AACR.©2016 American Association for Cancer Research.