Targeting of non-catalytic cysteine residues with covalent inhibitors is a powerful strategy for optimizing pharmacologic potency and selectivity on challenging targets such as the protein kinases. Nonetheless, concerns over off-target modification of proteins by irreversible covalent inhibitors leading to idiosyncratic toxicity has led to caution in applying this strategy to chronic diseases such as inflammation and autoimmune indication even though these events are rare. The utilization of covalent inhibitors that reversibly form an adduct with the protein cysteine is attractive as they may provide the pharmacodynamic and selectivity benefit with less propensity to form long-lived protein adducts. Herein we describe a strategy to design, optimize and characterize covalent, reversible inhibitors targeting Bruton's Tyrosine Kinase (Btk) and demonstrate their potential utility towards the treatment of inflammatory and autoimmune diseases. Structure-based drug design was utilized to optimize non-covalent inhibitor contacts within the kinase and guide placement of the covalent reactive group. Subsequent tuning of the reactivity and specificity of the electrophile resulted in the discovery of a class of highly selective Btk inhibitors within the cysteine homolog family. Through this strategy, we identified an orally bioavailable, potent and selective small molecule inhibitor of Btk which forms a covalent but reversible adduct with the enzyme as confirmed through enzymology, co-crystal structure analysis and mass spectroscopic characterization. The Btk inhibitor has been shown to be efficacious in several preclinical animal models of arthritis and autoimmune disease. This compound represents a new class of covalent Btk inhibitors which offers promise as a clinical candidate for the treatment of autoimmune and inflammatory diseases.

Targeted covalent-reversible inhibitors for the treatment of autoimmune and inflammatory disease: Application to Bruton's tyrosine kinase

245th National Meeting (2013)

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