Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B...

Hematopoietic cell kinase (HCK) and Bruton tyrosine kinase (BTK) are critical drivers of survival signaling in MYD88-mutated (MYD88^Mut) lymphomas. Building on our previously developed dual HCK/BTK inhibitor KIN-8194, we designed DFCI-002-06, a first-in-class proteolysis-targeting chimera (PROTAC) that potently and selectively degrades both kinases while retaining kinase inhibitory activity with improved selectivity versus KIN-8194. DFCI-002-06 induced enhanced apoptosis in MYD88^Mut lymphoma cells and remained active against ibrutinib-resistant BTK^Cys481 variants. The compound demonstrated high oral bioavailability in mice (F = 39%), favorable pharmacokinetics, and dose-dependent degradation of HCK and BTK in tumors. In TMD8 xenograft models, orally dosed DFCI-002-06 produced superior tumor suppression and prolonged survival compared to KIN-8194. Preclinical safety studies showed a favorable profile, including a negative Ames test, no hERG inhibition at relevant concentrations, and excellent tolerability in a 21 day rat toxicity study. DFCI-002-06 represents a rational dual-target degradation strategy for MYD88^Mut lymphomas.