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Precision Targeting of pten-Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing
Xuyu Liu1,2, Marcus J C Long3, Benjamin D Hopkins4
1School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
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.
Insights
Scientists developed a novel Akt3-selective inhibitor, MK-H(F)NE, using a native metabolite structure. This approach targets specific cancer subtypes like triple-negative breast cancer (TNBC) without common side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Off-target effects hinder targeted therapies, especially for closely related proteins like kinase isoforms involved in cancer.
- Akt isoforms (Akt1, Akt2, Akt3) have distinct roles in tumor subtypes, necessitating isoform-specific targeting.
Purpose of the Study:
- To develop a first-in-class Akt3-selective covalent inhibitor by exploiting Akt3's unique metabolite-sensing ability.
- To demonstrate the inhibitor's efficacy and specificity against Akt3 in cancer models, particularly triple-negative breast cancer (TNBC).
Main Methods:
- Designed an inhibitor (MK-H(F)NE) with an electrophilic core derived from the native lipid metabolite HNE.
- Conducted mechanistic profiling and pathway interrogations to understand isoform selectivity.
- Evaluated inhibitor performance in TNBC xenografts and compared it to pan-Akt inhibitors.
Main Results:
- MK-H(F)NE demonstrated functional Akt3 selectivity, retaining the native metabolite's structure for bias.
- The inhibitor showed tumor-subtype specificity against pten-null TNBC.
- MK-H(F)NE exhibited superior performance in TNBC xenografts compared to pan-Akt inhibitors, without Akt1-related side effects.
Conclusions:
- Inhibitors derived from native metabolite sensing are effective for targeting specific kinase isoforms.
- This strategy enables the identification of novel Akt3-specific targets and facilitates tumor-subtype-specific interventions.
- MK-H(F)NE represents a promising therapeutic strategy for Akt3-driven cancers like TNBC.
