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Precision Targeting of pten -Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing.
- Source :
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ACS central science [ACS Cent Sci] 2020 Jun 24; Vol. 6 (6), pp. 892-902. Date of Electronic Publication: 2020 May 20. - Publication Year :
- 2020
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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.<br />Competing Interests: The authors declare the following competing financial interest(s): Akt-inhibitors discussed in this work was filed for US Patent application by the former institution of X.L., M.J.C.L., and Y.A., Cornell University.<br /> (Copyright © 2020 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 2374-7943
- Volume :
- 6
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS central science
- Publication Type :
- Academic Journal
- Accession number :
- 32607436
- Full Text :
- https://doi.org/10.1021/acscentsci.9b00893