Author/Authors :
Milhollen، نويسنده , , Michael A. and Thomas، نويسنده , , Michael P. and Narayanan، نويسنده , , Usha and Traore، نويسنده , , Tary and Riceberg، نويسنده , , Jessica and Amidon، نويسنده , , Benjamin S. and Bence، نويسنده , , Neil F. and Bolen، نويسنده , , Joseph B. and Brownell، نويسنده , , James R. Dick، نويسنده , , Lawrence R. and Loke، نويسنده , , Huay-Keng and McDonald، نويسنده , , Alice A. and Ma، نويسنده , , Jingya and Manfredi، نويسنده , , Mark G. and Sells، نويسنده , , Todd B. and Sintchak، نويسنده , , Mike D. and Yang، نويسنده , , Xiaofeng and Xu، نويسنده , , Qing and Koenig، نويسنده , , Erik M. and Gavin، نويسنده , , James M. and Smith، نويسنده , , Peter G.، نويسنده ,
Abstract :
Summary
4 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 NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ 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 NAEβ mutations.
