J Med Chem. 2019 Sep 12;62(17):7923-7940. doi: 10.1021/acs.jmedchem.9b00687. Epub 2019 Aug 19.
Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound (, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
Btk 的异常激活在 B 细胞淋巴瘤的发病机制中起着重要作用，这表明抑制 Btk 可用于治疗血液系统恶性肿瘤。发现更具选择性的靶向共价 Btk 抑制剂具有很高的价值。在此，我们通过使用体外效力、选择性、药代动力学 (PK) 和体内药效学来优先考虑化合物，披露了一种强效、选择性和不可逆的 Btk 抑制剂的发现和临床前特征，作为我们的临床候选药物。化合物 （，zanubrutinib）表现出：(i) 对 Btk 具有强大的活性和对其他 Tec、EGFR 和Src 家族激酶的优异选择性，(ii) 理想的 ADME，在小鼠体内具有良好的药效学和在 OCI-LY10 异种移植模型中的疗效。
