2‑Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases

Lysine-targeting irreversible covalent inhibitors have
attracted
growing interests in recent years, especially in the fields of kinase
research. Despite encouraging progress, few chemistries are available
to develop inhibitors that are exclusively lysine-targeting, selective,
and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based,
lysine-targeting strategy to generate potent and selective small-molecule
inhibitors of ABL kinase by selectively targeting the conserved catalytic
lysine in the enzyme. We showed the resulting compounds were cell-active,
capable of covalently engaging endogenous ABL kinase in K562 cells
with long-residence time and few off-targets. We further validated
the generality of this strategy by developing EBA-based irreversible
inhibitors against EGFR (a kinase) and Mcl-1 (a nonkinase) that covalently
reacted with the catalytic and noncatalytic lysine within each target.