RESUMO
Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the "Design" phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.
Assuntos
Carbamatos , Desenho de Fármacos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-cbl , Proteínas Proto-Oncogênicas c-cbl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Carbamatos/química , Carbamatos/farmacologia , Carbamatos/síntese química , Humanos , Relação Estrutura-Atividade , Modelos Moleculares , Inteligência Artificial , Descoberta de Drogas , Proteínas Adaptadoras de Transdução de SinalRESUMO
Visible-light-activated electron donor-acceptor complexes offer distinct reaction pathways for the synthesis of complex molecules under mild conditions. Herein, we report a method for the reductive generation of α-amino radicals via the reaction of a visible-light-activated ion-pair charge-transfer complex formed between an in situ-generated alkyl-iminium ion and a thiophenolate. This distinct activation mode is demonstrated through the development of a multicomponent coupling reaction to form substituted aminomethyl-cyclopentanes from secondary amines, cyclopropyl aldehydes, and alkenes. The operationally straightforward transformation displays broad scope and provides a means to generate cyclic amine-containing scaffolds from readily available feedstocks.