RESUMO
Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 µM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Metionil Aminopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Metais/química , Metionina/química , Camundongos Nus , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.