KPT-9274 Sample Clauses

KPT-9274. KPT-9274 is a first-in-class orally bioavailable small molecule that is a non-competitive dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase/PBEF/visfatin (NAMPT). Co-inhibition of these targets leads to synergistic anti-tumor effects through energy depletion, inhibition of deoxyribonucleic acid (DNA) repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells are more resistant to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic rates. KPT-9274 demonstrated potent anti-proliferative activity against cancer cell lines (solid tumor cells MTT median IC50: 135 nM, range 0.007 to >10 µM; hematological cancer cells MTT median IC50: 40 nM, range 0.003 to >10 µM) with minimal toxicity to normal cells (median MTT IC50: ~0.9 µM, range 0.033 to >10 µM). In mouse xenograft studies, KPT-9274 (oral 50-200 mg/kg twice daily for 5 days/week) was well tolerated and resulted in a marked reduction in tumor size across a variety of tumors, including colon, pancreatic, lung, multiple myeloma, leukemia, and lymphoma. In approximately half of the tumor types studied, complete elimination of tumors in as short as 3 weeks was observed with no regrowth after cessation of treatment (up to 3 weeks). In other cell types tumor growth inhibition was observed. KPT-9274 was able to control systemic acute B lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML) tumor growth and significantly extended overall survival. Moreover, KPT-9274 has shown preliminary efficacy in companion dogs with spontaneous advanced lymphomas and multiple myeloma (MM). Unlike the Pan-PAK inhibitor (PF-3758309), or the NAMPT inhibitors (APO866 and GMX1777/GMX1778) that advanced to human clinical trials, the dual NAMPT/PAK inhibitor KPT-9274 demonstrates consistent pharmacokinetic (PK) properties (e.g., oral absorption), exhibits minimal brain penetration, and does not inhibit any of the cytochrome P450 (CYP450) enzymes. The nonclinical toxicity profile of KPT-9274 recapitulates the expected class level gastrointestinal (GI) and hematopoietic toxicities but not the retinal and cardiac effects observed preclinically with some NAMPT inhibitors. The lack of retinal and cardiac effects of KPT-9274 may be attributed to its minimal permeability and decreased potency compared to other NAMPT inhibitors. Furthermore, no orally available PAK4 selective inhibitors have been develo...