Drugs targeting Bruton’s tyrosine kinase (BTK) are recognized as key tools in hematological oncology. The clinical efficacy of BTK inhibitors is limited, however, by the emerging resistance driven by BTK mutations and the severe toxicity attributed to off-target kinase inhibition. PROteolysis TArgeting Chimeras (PROTACs) offer an alternative modality to address these major drawbacks. Herein, we present novel BTK-targeting PROTACs with a high potency against both the wild-type and the mutated BTK. Novel CRBN-binding warheads have been developed to mitigate the off-target protein degradation associated with anchors derived from thalidomide analogues. The linker optimization effort resulted in a series of potent, orally bioavailable BTK-targeting PROTACs without concomitant activity against IKZF1, IKZF3, and GSPT1. The lead compounds ISM-PR25 and ISM-PR44 demonstrate sufficient efficacy in degrading BTK protein in malignant B cells (DC50 = 0.04 and 0.05 nM, respectively) associated with a favorable DMPK profile and a large safety window regarding cell toxicity and effectively degraded BTK in mouse circulating B cells by single-dose oral treatment (3 mg/kg).
