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

Xuyu Liu; Marcus J C Long; Benjamin D Hopkins; Chaosheng Luo; Lingxi Wang; Yimon Aye

doi:10.1021/acscentsci.9b00893

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

ACS Cent Sci. 2020 Jun 24;6(6):892-902. doi: 10.1021/acscentsci.9b00893. Epub 2020 May 20.

Authors

Xuyu Liu^{1

2}, Marcus J C Long³, Benjamin D Hopkins⁴, Chaosheng Luo⁵, Lingxi Wang⁵, Yimon Aye⁵

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
² The Heart Research Institute, Newtown, New South Wales 2042, Australia.
³ Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14850, United States.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
⁵ Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.

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.