title: Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924.
abstract: 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 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.
authors.affiliation: Discovery, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Milhollen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Usha
authors.initials: U
authors.lastname: Narayanan
authors.forename: Tary
authors.initials: T
authors.lastname: Traore
authors.forename: Jessica
authors.initials: J
authors.lastname: Riceberg
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Amidon
authors.forename: Neil F
authors.initials: NF
authors.lastname: Bence
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Bolen
authors.forename: James
authors.initials: J
authors.lastname: Brownell
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Dick
authors.forename: Huay-Keng
authors.initials: HK
authors.lastname: Loke
authors.forename: Alice A
authors.initials: AA
authors.lastname: McDonald
authors.forename: Jingya
authors.initials: J
authors.lastname: Ma
authors.forename: Mark G
authors.initials: MG
authors.lastname: Manfredi
authors.forename: Todd B
authors.initials: TB
authors.lastname: Sells
authors.forename: Mike D
authors.initials: MD
authors.lastname: Sintchak
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Erik M
authors.initials: EM
authors.lastname: Koenig
authors.forename: James M
authors.initials: JM
authors.lastname: Gavin
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003517:Cyclopentanes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D044764:Ubiquitin-Activating Enzymes / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C539933:pevonedistat