Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
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DOI：
10.1021/acs.jmedchem.5b01346
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发表时间：
2015-12-24
影响因子：
7.3
通讯作者：
Wustrow, David
中科院分区：
文献类型：
--
作者：
Zhou, Han-Jie;Wang, Jinhai;Wustrow, David
aaa - atp酶p97在蛋白质稳态机制中发挥重要作用，包括泛素蛋白酶体系统（ups）介导的蛋白质降解、内质网相关降解（BRAD）和自噬。在此，我们描述了我们的主要优化工作，重点是体外效价，ADME和药物特性，从而发现了一种有效的，atp竞争性的，d2选择性的，口服生物可利用的p97抑制剂71，CB-6083。用71治疗肿瘤细胞会导致与抑制UPS和ERAD功能相关的标志物的显著积累，从而诱导不可解决的蛋白毒性应激和细胞死亡。在携带肿瘤的小鼠中，口服71可引起未折叠蛋白反应（UPR）标记物的快速积累，随后诱导细胞凋亡，从而在体内、实体瘤和血液学肿瘤的异种移植模型中产生持续的抗肿瘤活性。71已在多发性骨髓瘤和实体瘤患者中进入I期临床试验。
The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin proteasome system (ups) mediated protein degradation, endoplasmic reticulum-associated degradation (BRAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-6083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell, death. In tumor bearing mice, oral administration of 71 causes rapid accumulation Of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to Sustained antitumor activity in in vivo, xenograft models of both solid and hematological tumors. 71 has been taken into phase I clinical trials in patients with multiple myeloma and solid tumors.