Precision Targeting of pten-Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing.

ABSTRACT: Off-target effects continue to impede disease interventions, particularly when targeting a specific protein within a family of similar proteins, such as kinase isoforms that play tumor-subtype-specific roles in cancers. Exploiting the specific electrophilic-metabolite-sensing capability of Akt3, versus moderate or no sensing, respectively, by Akt2 and Akt1, we describe a first-in-class functionally Akt3-selective covalent inhibitor [MK-H(F)NE], wherein the electrophilic core is derived from the native reactive lipid metabolite HNE. Mechanistic profiling and pathway interrogations point to retention of the metabolite's structure-as opposed to implicit electrophilicity-as being essential for biasing isoform preference, which we found translates to tumor-subtype specificity against pten

SUBMITTER: Liu X 

PROVIDER: S-EPMC7318068 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature