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

Hematopoietic cell kinase (HCK) and Bruton tyrosine kinase
(BTK)
are critical drivers of survival signaling in MYD88-mutated (MYD88Mut) 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 MYD88Mut lymphoma cells and remained active against ibrutinib-resistant BTKCys481 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 MYD88Mut lymphomas.