Review maps covalent kinase inhibitors across EGFR, BTK, FGFR and JAK3
- This is a review article, not a primary study, covering 35 approved and investigational covalent kinase inhibitors.
- It focuses on four families that target a non-catalytic cysteine near the ATP pocket: EGFR (Cys797), BTK (Cys481), FGFR (Cys488) and JAK3 (Cys909).
- Each inhibitor is discussed for discovery history, binding mode, SAR, indications and synthesis, along with off-target toxicity and acquired resistance such as EGFR C797S.
💡 Points
Four cysteines, four very different risk profiles. Cys481 in BTK and Cys797 in EGFR are well-validated handles, but the C797S escape mutation shows the weakness: lose the nucleophile and the whole warhead strategy collapses, so reversible or allosteric backups matter. JAK3's Cys909 is the interesting one, since it can buy isoform selectivity that ATP-site binders struggle with, though acrylamide reactivity across the kinome remains the tox question.