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Cancer Cell ; 21(3): 388-401, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22439935

RESUMO

MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEß as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEß mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEß mutations.


Assuntos
Ciclopentanos/farmacologia , Inibidores Enzimáticos/farmacologia , Mutação , Pirimidinas/farmacologia , Enzimas Ativadoras de Ubiquitina/genética , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Ratos , Ratos Nus , Células Tumorais Cultivadas , Enzimas Ativadoras de Ubiquitina/química , Enzimas Ativadoras de Ubiquitina/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
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