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

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

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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