REDX08608: A Potent and Selective BTK Inhibitor Effective Against Wild-Type and Mutant C481S BTK in Oncology

The study introduces REDX08608, a novel BTK inhibitor developed to address resistance mechanisms in B-cell malignancies. This compound is potent and selective, capable of inhibiting both wild-type and C481S mutated BTK, which is crucial for overcoming resistance seen in patients with CLL progression after ibrutinib treatment. REDX08608 demonstrates nanomolar binding affinity and potency in various assays and effectively inhibits BTK signaling and growth in cell lines reliant on the BTK pathway, including primary CLL cells. It also suppresses B-cell activation in human blood and PBMCs at nanomolar concentrations.

The compound has been shown to be highly selective against a panel of 468 kinases, with significant selectivity against Tec and Src kinase family members and EGFR. REDX08608 has undergone comprehensive DMPK profiling, revealing acceptable metabolic and plasma stability across different species. It does not activate PXR or exhibit time-dependent inhibition, and it has a favorable profile for cytochrome P450 inhibition. The compound has demonstrated good exposure, oral bioavailability, and half-life in preclinical models, with dose linearity assessed in mice, rats, and dogs.

The study concludes that REDX08608 is a promising reversible BTK inhibitor with potential efficacy in targeting both wild-type and resistant forms of BTK in lymphoma cell lines. The disclosures section indicates that multiple authors are employed by Redx Oncology Ltd - Redx Pharma Plc, with some also having research funding connections to other pharmaceutical companies.