Covalent inhibition is a powerful strategy to develop potent and selective small molecule kinase inhibitors. Targeting the conserved catalytic lysine is an attractive method for selective kinase inactivation. Inspired by previous results, we have developed novel inhibitors of phosphoinositide 3-kinase δ (PI3Kδ) which covalently modify the catalytic lysine, Lys779, using activated esters as the reactive electrophiles to promote lysine acylation (Figure 1). The acylating agents were prepared by adding the activated ester motif to a known selective dihydroisobenzofuran PI3Kδ inhibitor. Various esters were designed, including an acetyl ester which was the smallest lysine modification we were interested in evaluating. Covalent binding to the kinase was characterised by protein mass spectrometry of the PI3Kδ-ester adducts. Acylation of Lys779 was confirmed by enzymatic digest followed by liquid chromatography-tandem mass spectrometry. Biochemical data confirmed that PI3Kδ inhibition was a direct result of covalent lysine acylation. These promising results suggest that a chemical modification of lysine as minor as acetylation is sufficient to inactivate kinase activity. Due to the conserved nature of the catalytic lysine across kinases, we believe this inhibition strategy could be applicable to a broad range of clinically relevant targets.

Acetylation of the catalytic lysine inhibits kinase activity in PI3Kδ

ACS Fall 2020 Virtual Meeting

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