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⁺) and U937 (FLT3^WT) and induced cell death in MOLM13 (FLT3^ITD) and even in MOLM13 (FLT3^ITD, D835Y), 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