2. Academic Validation
  3. Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations

Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations

  • Blood Cancer J. 2026 May 7;16(1):107. doi: 10.1038/s41408-026-01509-8.
Natalia Timofeeva 1,  Breana Herrera 1,  Hitomi Fujiwara 2,  Tokiko Asami 2,  Hiroko Endo 2,  Mariko Hatakeyama 2,  Fumio Nakajima 2,  Hiroshi Ohmoto 2,  Yu Nishioka 2,  Kyoko Miyamoto 3,  Akinori Arimura 2 3,  Shady I Tantawy 1 4,  Javier Pinilla-Ibarz 5,  Catherine C Coombs 6,  Nitin Jain # 7,  Masaaki Sawa # 2,  Varsha Gandhi # 8 9
Affiliations

Affiliations

  • 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Carna Biosciences, Inc., Kobe, Japan.
  • 3 CarnaBio USA Inc., South San Francisco, CA, USA.
  • 4 Internal Medicine and Clinical Hematology Department, Suez Canal University, Ismailia, Egypt.
  • 5 Moffitt Cancer Center, Tampa, FL, USA.
  • 6 University of California, Irvine, CA, USA.
  • 7 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 9 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 42098067 DOI: 10.1038/s41408-026-01509-8
Abstract

Btk inhibitors (BTKi) have become standard of care for treatment of patients with chronic lymphocytic leukemia (CLL). Covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are effective but alterations in the kinase domain at C481 or Btk gatekeeper residue T474 mutations result in development of resistance. Noncovalent Btk inhibitors (ncBTKi) such as pirtobrutinib are effective in patients with C481x mutations developed through use of cBTKi. However, resistance to ncBTKi can occur owing to second site aberrations in Btk, generating novel mutations such as L528x and T316x. Sometimes, CLL cells with double Btk mutations are also observed. These Btk aberrations underscore a need for new inhibitors that target pan-BTK-mutants. We evaluated the efficacy of a new ncBTKi, docirbrutinib (AS-1763), against 14 Btk mutants, including C481S, T474x, and L528x, as well as gatekeeper and kinase domain double mutants, using biochemical assays, cell-line models, and primary CLL lymphocytes. Docirbrutinib potently inhibited Btk autophosphorylation and mutant BTK-driven cell proliferation, with greater effects than ibrutinib and pirtobrutinib against certain mutants. In treatment-naïve and relapsed/refractory CLL samples, docirbrutinib disrupted B-cell receptor signaling and sensitized cells to Apoptosis induced by venetoclax and AZD5991. In a dose-escalation trial (NCT05602363), docirbrutinib decreased CCL3/CCL4 biomarkers and inhibited the B-cell receptor pathway signaling in longitudinal samples from patients with relapsed/refractory CLL. These findings establish docirbrutinib as a pan-mutant ncBTKi with potential to improve outcomes for CLL patients, including those with disease resistant to cBTKi and Other ncBTKi.

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