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Drug Discov Today ; 17(13-14): 733-40, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22425710


In this paper, we review the key solutions that enabled evolution of the lead optimization screening support process at Bristol-Myers Squibb (BMS) between 2004 and 2009. During this time, technology infrastructure investment and scientific expertise integration laid the foundations to build and tailor lead optimization screening support models across all therapeutic groups at BMS. Together, harnessing advanced screening technology platforms and expanding panel screening strategy led to a paradigm shift at BMS in supporting lead optimization screening capability. Parallel SAR and structure liability relationship (SLR) screening approaches were first and broadly introduced to empower more-rapid and -informed decisions about chemical synthesis strategy and to broaden options for identifying high-quality drug candidates during lead optimization.

Descoberta de Drogas/métodos , Indústria Farmacêutica/organização & administração , Preparações Farmacêuticas , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/organização & administração , Animais , Descoberta de Drogas/economia , Indústria Farmacêutica/economia , Indústria Farmacêutica/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eficiência Organizacional , Ensaios de Triagem em Larga Escala , Humanos , Investimentos em Saúde , Preparações Farmacêuticas/química , Relação Estrutura-Atividade , Tecnologia Farmacêutica/economia
J Comput Aided Mol Des ; 19(2): 111-22, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16075305


Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors.

CDC2-CDC28 Quinases/antagonistas & inibidores , Ciclina A/antagonistas & inibidores , Ciclina D1/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinonas/farmacologia , Sequência de Aminoácidos , CDC2-CDC28 Quinases/química , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Quinases Ciclina-Dependentes/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ligações de Hidrogênio , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas/química , Pirimidinonas/química , Homologia de Sequência de Aminoácidos , Especificidade por Substrato