Zhao Yunpeng, Shu Yongzhi, Lin Jun, Chen Zhendong, Xie Qiong, Bao Yanning, Lu Lixue, Sun Nannan, Wang Yonghui
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Shanghai Meizer Pharmaceuticals Co., Ltd, 58 Yuanmei Road, Shanghai, 201109, China.
Eur J Med Chem. 2021 Dec 5;225:113820. doi: 10.1016/j.ejmech.2021.113820. Epub 2021 Sep 2.
Bruton's tyrosine kinase (BTK) is a key drug target for B-cell related malignancies. Irreversible covalent BTK inhibitors have been approved for the treatment of B-cell malignancies, yet BTK C481S mutation at the covalent binding site has caused drug-resistance of BTK covalent binding inhibitors. The proteolysis targeting chimera (PROTAC) technology increases the sensitivity to drug-resistant targets compared to classic inhibitors, which provides a new strategy for mutant BTK related B-cell malignancies. ARQ531, a reversible non-covalent BTK inhibitor that inhibits wild type (WT) and mutated BTK with high selectivity, could be an ideal warhead for PROTACs targeting the mutant BTK. Herein, we designed a novel series of PROTACs using the selective non-covalent BTK inhibitor ARQ531 as warhead, with the goal of improving the degradation of both wild-type and C481S mutant BTKs, and increasing the selectivity of BTK over other kinases. This effort will provide some basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of B-cell lymphomas.
布鲁顿酪氨酸激酶（BTK）是B细胞相关恶性肿瘤的关键药物靶点。不可逆共价BTK抑制剂已被批准用于治疗B细胞恶性肿瘤，但共价结合位点的BTK C481S突变导致了BTK共价结合抑制剂的耐药性。与传统抑制剂相比，靶向嵌合体蛋白（PROTAC）技术提高了对耐药靶点的敏感性，为与突变BTK相关的B细胞恶性肿瘤提供了新策略。ARQ531是一种可逆的非共价BTK抑制剂，对野生型（WT）和突变型BTK具有高选择性抑制作用，可能是靶向突变BTK的PROTAC的理想弹头。在此，我们以选择性非共价BTK抑制剂ARQ531为弹头设计了一系列新型PROTAC，目的是提高野生型和C481S突变型BTK的降解效率，并增加BTK相对于其他激酶的选择性。这将为BTK PROTAC作为治疗B细胞淋巴瘤的新策略的进一步临床前研究提供一些依据。
