Precision Targeting of pten-Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing.
ACS Cent Sci
; 6(6): 892-902, 2020 Jun 24.
Article
in En
| MEDLINE
| ID: mdl-32607436
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-null triple-negative breast cancers (TNBCs). MK-H(F)NE further enables novel downstream target identification specific to Akt3-function in disease. In TNBC xenografts, MK-H(F)NE fares better than reversible pan-Akt-inhibitors and does not show commonly observed side-effects associated with Akt1-inhibition. Inhibitors derived from native-metabolite sensing are thus an enabling plan-of-action for unmasking kinase-isoform-biased molecular targets and tumor-subtype-specific interventions.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Cent Sci
Year:
2020
Document type:
Article
Affiliation country:
Australia