Treatment-Emergent Mutations in NAE
Menée in vitro et à l'aide de xénogreffes, cette étude identifie un mécanisme de résistance à un nouveau composé appelé MLN4924, une petite molécule inhibant l'enzyme NAE
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 NAE
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as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAE
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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 NAE
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mutations. º Treatment-emergent mutations in NAE
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confer resistance to MLN4924 º Amino acid substitution A171T in the adenylate binding site is the most frequent mutation º NAE
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mutants reduce inhibitor potency and decrease affinity of NEDD8-MLN4924 adduct º A tight-binding pan-E1 inhibitor overcomes resistance in NAE
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mutant cells