title: Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
abstract: We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 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 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
authors.affiliation: Departments of †Therapeutic Discovery, ‡Oncology Research, §Pharmaceutics, and ∥Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
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authors.forename: Xiaoning
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authors.forename: Dineli
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authors.lastname: Wickramasinghe
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mesh_terms: D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D020298:U937 Cells; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C000589290:2-hydroxy-1-(2-((9-(4-methylcyclohexyl)-9H-pyrido(4',3'-4,5)pyrrolo(2,3-d)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanone; D065692:Cytochrome P-450 CYP3A Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6