HZ-A-005, a potent, selective, and covalent Bruton’s tyrosine kinase inhibitor in preclinical development

[Display omitted] •A potent and irreversible BTK inhibitor with more than 50-fold selectivity against ITK, EFGR(L858R).•IC50 on five tumor cell lines is less than 1 μM.•HZ-A-005 markedly decreases tumor growth in xenograft mouse models.•The Cmax of HZ-A-005 after administration is about 2-fold than ibrutinib. Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec kinases family and is essential for B cell receptor (BCR) mediated signaling. BTK inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. Here we disclose a potent, selective, and covalent BTK inhibitor, HZ-A-005, currently in preclinical development. HZ-A-005 demonstrated dose-dependent activity in two xenograft models of lymphoma in vivo. It showed highly favourable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical studies. On the basis of its potency, selectivity, and covalent mode of inhibition, HZ-A-005 reveals the potential to be a promising BTK inhibitor for a wide range of cancer indications.