PD173955

Enzyme inhibitor

This tyrosine kinase inhibitor (FW = 443.35 g/mol; CAS 260415-63-2; Solubility: <1 mg/mL DMSO, Ethanol, H2O), 6-(2,6-dichlorophenyl)-8- methyl-2-((3-(methylthio)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one targets Bcr-Abl (IC50 = 1-2 nM, in vitro), the constitutively active tyrosine kinase that results from inadvertent fusion of bcr and abl genes and that causes oncogenic transformation in chronic myelogenous leukemia, or CML, inhibiting Bcr-Abl-dependent cell growth with an IC50 of 2-35 nM in different cell lines. PD173955 also inhibits kit ligand-dependent c-kit autophosphorylation (IC50 = ~25 nM) and kit ligand-dependent proliferation of M07e cells (IC50 = 40 nM), but had a lesser effect on interleukin 3- dependent (IC50 = 250 nM) or granulocyte macrophage colony-stimulating factor (IC50 = 1 μM)-dependent cell growth. PD173955 also increases the susceptibility of HT29 cells to detachment-induced apoptosis (anoikis) in a dose- and time-dependent manner. Structural Features Distinguishing Imatinib & PD173955 Binding: Crystal structures of Abl kinase domain complexes with imatinib (Gleevec) and PD173955 show that both bind to the canonical ATP-binding site, but in distinctive ways. Imatinib captures a specific inactive conformation of Abl’s activation loop, mimicking the bound peptide substrate. In contrast, PD173955 binds to the Abl activation loop in a way that resembles the active kinase conformation. The 10x greater potency of PD173955 over imatinib is attributed to its ability to target multiple active and inactive forms of Abl, whereas imatinib binds only to a specific catalytically inactive conformation (4