Other kinases with homologous cysteine

Other kinases with homologous cysteine refers to a group of protein kinases characterized by a structurally conserved cysteine residue at a specific position within the ATP-binding pocket, typically equivalent to Cys-481 in Bruton's Tyrosine Kinase (BTK) or Cys-797 in the Epidermal Growth Factor Receptor (EGFR) (Honigberg et al., 2010, PNAS). This group includes the TEC family kinases (BTK, ITK, TEC, BMX, and TXK), members of the EGFR family (EGFR, HER2, and HER4), and others such as JAK3 and BLK (UniProt; Singh et al., 2011, Nature Reviews Drug Discovery). These kinases are significant therapeutic targets because the nucleophilic nature of the cysteine thiol allows for the design of covalent inhibitors that form a stable, irreversible bond with the enzyme. This mechanism leads to high potency and prolonged pharmacodynamics that are independent of the drug's systemic half-life (FDA Label: Imbruvica). However, the conservation of this residue across multiple kinases can lead to off-target toxicities, such as atrial fibrillation or bleeding, which are often attributed to the unintended inhibition of other family members like TEC (Chen et al., 2018, Journal of Hematology & Oncology). Furthermore, clinical resistance to these therapies frequently arises through mutations that replace the target cysteine with a non-nucleophilic residue, such as serine, thereby preventing covalent bond formation (Woyach et al., 2014, NEJM). Understanding this group is essential for developing next-generation inhibitors with improved selectivity profiles.

Other names

Cysteine-containing kinasesKinases with a conserved active-site cysteineTEC family and homologsCovalent kinase targets

Irreversible covalent inhibition via Michael addition to a conserved cysteine residue (e.g., Cys-481 in BTK or Cys-797 in EGFR) within the ATP-binding pocket.