Targeting MYD88 Mutated B-Cell Lymphomas: The Potency and Selectivity of the Dual HCK and BTK Inhibitor Kin-8194 in Overcoming Ibrutinib Resistance

A newly developed non-covalent dual inhibitor, KIN-8194, has been shown to target HCK and BTK effectively. It was identified through an extensive screening process and subsequent optimization of over 400 synthesized analogs. The inhibitor demonstrated potent suppression of HCK and BTK with low IC50 values and was able to block the activity of these proteins in various cell types, including those with MYD88 mutations and ibrutinib resistance. KIN-8194 also displayed selective cytotoxicity against MYD88 mutated cells and overcame ibrutinib resistance.

The compound exhibited favorable pharmacokinetic properties in mice, including high bioavailability, a long serum half-life, and suitable drug clearance for once-daily oral dosing. Safety profiling indicated no significant off-target effects, negative AMES results, and acceptable Cyp inhibition levels. Pharmacodynamic studies confirmed that KIN-8194 could block the activity of HCK and BTK in vivo, and continuous dosing was well tolerated.

In xenograft models using mice, KIN-8194 significantly reduced tumor growth and improved survival rates compared to control groups or those treated with ibrutinib. Remarkably, in some cases, complete tumor elimination was achieved, suggesting a potential curative effect. The study highlights KIN-8194 as a promising non-covalent dual HCK and BTK inhibitor with a favorable safety profile, capable of selectively targeting MYD88 mutated cells and overcoming resistance to ibrutinib.

Disclosures were made regarding consultancy and research funding connections to various pharmaceutical companies for several individuals involved in the study.