In vitro activity: TP-3654 is a novel and potent inhibitor of Pim-1 and Pim-3 ( proviral integration site for moloney murine leukemia virus) kinase that is potentially useful for the treatment of various cancers such as prostate cancer, acute myeloid leukemia, multiple sclerosis and psoriasis. As a second-generation PIM inhibitor, TP-3654 displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 demostrates favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.

Kinase Assay: TP-3654 is a second-generation Pim kinase inhibitor with Ki values of 5 and 42 nM for Pim-1 and Pim-3, respectively.

Cell Assay: TP-3654 displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 demostrates favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. 1 μM TP-3654 is tested against 336 kinases at a concentration of 10 μM ATP. IC50 determinations of phosphoinositide 3-kinase (PI3K) (α, β, δ, and γ) and all kinases inhibited by>50% from the initial screen are performed using 10-dose, three-fold serial dilutions of TP-3654 starting with 10 μM at Km ATP concentrations for each kinase