Discovery of HBW-3-10: A potent, orally active, reversible Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in mice.

• DOI: 10.1200/jco.2021.39.15_suppl.e15062
• Publication Date: 2021-06-02T14:02:23Z
• Authors: Ning Lee; Yingfu Li; Chester Yuan; Guanfeng Liu; Chunchao Yue
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

e15062 Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), several years. However, CLL patients who used may develop drug resistance due to acquired mutations, in particular C481S that directly impacts binding ibrutinib. In recent years, efforts have made second reversible inhibitors are effective against both wild-type and mutated B-cell malignancies. LOXO-305 ARQ-531 two examples advanced clinical trials ibrutinib-resistant CLL. Methods: New were designed, synthesized tested enzymatic activities C481S-mutated BTK. Highly active compounds confirmed growth effects diffuse large lymphoma derived TMD8 cells. Their microsomal stability ADME properties also assessed. Potent bioavailable further evaluated vivo efficacy using a xenograft tumor model mice. A 14-day toxicity study rats was performed correspondingly. Results: As shown table, HBW-3-10 greater potency pharmacokinetic profile (rats, 10mg/kg PO) than ARQ-531. mouse study, HBW-3-10, compared directly, all dosed at QD, resulting inhibition rates (TGI) 38.3%, 9.3% 22.5%, respectively. Based on our data, is more efficacious preliminary experiment rats, 100mg/kg QD. Animals ARQ531 group started showing signs sickness day 3, died 6 toxicity; contrast, no animal showed any sign or during entire course study. Conclusions: We discovered novel superior preclinical profile, safety other known ones. provides valuable candidate treating Ibrutinib resistant beyond![Table: see text]