3 research outputs found
Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3
We
describe the structural optimization of a lead compound <b>1</b> that exhibits dual inhibitory activities against FLT3 and
CDK4. A series of pyrido[4′,3′:4,5]pyrrolo[2,3-<i>d</i>]pyrimidine derivatives was synthesized, and SAR analysis,
using cell-based assays, led to the discovery of <b>28</b> (<b>AMG 925</b>), a potent and orally bioavailable dual inhibitor
of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound <b>28</b> inhibits the proliferation of a panel of human tumor cell
lines including Colo205 (Rb<sup>+</sup>) and U937 (FLT3<sup>WT</sup>) and induced cell death in MOLM13 (FLT3<sup>ITD</sup>) and even
in MOLM13 (FLT3<sup>ITD, D835Y</sup>), which exhibits resistance
to a number of FLT3 inhibitors currently under clinical development.
At well-tolerated doses, compound <b>28</b> leads to significant
growth inhibition of MOLM13 xenografts in nude mice, and the activity
correlates with inhibition of STAT5 and Rb phosphorylation