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

  • J Med Chem. 2026 Jan 22;69(2):1119-1134. doi: 10.1021/acs.jmedchem.5c02444.
John M Hatcher  1  2 ,  Shirong Liu  1  2 ,  Amanda Kofides  1 ,  Alexa Canning  1 ,  Dominic Pizzarella  1 ,  Xia Liu  1 ,  Nickolas Tsakmaklis  1 ,  Maria Guerrera  1  2 ,  Christopher Patterson  1 ,  Alberto Guijosa  1  2 ,  Prafulla Gokhale  3 ,  Zachary Hunter  1  2 ,  Shayna Sarosiek  1  2 ,  Jorge Castillo  1  2 ,  Jinhua Wang  4 ,  Sara J Buhrlage  4 ,  Steven P Treon  1  2
Affiliations
  • 1. Bing Center for Waldenströms Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 3. Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4. Department of Cancer Biology, Harvard Medical School, Dana-Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts 02115, United States.
PMID: 41482966 DOI: 10.1021/acs.jmedchem.5c02444
Abstract

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.

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