A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas

摘要: The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine that involved in a number of signaling pathways important to cancer cells. PIM act downstream effector functions as inhibitors apoptosis positive regulators G1-S phase progression through the cell cycle. upregulated multiple indications, including lymphoma, leukemia, myeloma, prostate, gastric, head neck cancers. Overexpression one or more family members patient tumors frequently correlates with poor prognosis. aim this investigation was evaluate expression low- high-grade urothelial carcinoma assess role function disease their potential serve molecular targets therapy. One hundred thirty-seven cases were included study surgical biopsy resection specimens. High levels all three observed both noninvasive invasive carcinomas. second-generation inhibitor, TP-3654, displays submicromolar activity pharmacodynamic biomarker modulation, proliferation studies, colony formation assays using UM-UC-3 bladder line. TP-3654 favorable human ether-a-go-go-related gene cytochrome P450 inhibition profiles compared first-generation SGI-1776, exhibits oral bioavailability. In vivo xenograft studies line show kinase can reduce tumor growth, suggesting may be active