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Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-12-04 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01346 Han-Jie Zhou 1 , Jinhai Wang 1 , Bing Yao 1 , Steve Wong 1 , Stevan Djakovic 1 , Brajesh Kumar 1 , Julie Rice 1 , Eduardo Valle 1 , Ferdie Soriano 1 , Mary-Kamala Menon 1 , Antonett Madriaga 1 , Szerenke Kiss von Soly 1 , Abhinav Kumar 1 , Francesco Parlati 1 , F. Michael Yakes 1 , Laura Shawver 1 , Ronan Le Moigne 1 , Daniel J. Anderson 1 , Mark Rolfe 1 , David Wustrow 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-12-04 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01346 Han-Jie Zhou 1 , Jinhai Wang 1 , Bing Yao 1 , Steve Wong 1 , Stevan Djakovic 1 , Brajesh Kumar 1 , Julie Rice 1 , Eduardo Valle 1 , Ferdie Soriano 1 , Mary-Kamala Menon 1 , Antonett Madriaga 1 , Szerenke Kiss von Soly 1 , Abhinav Kumar 1 , Francesco Parlati 1 , F. Michael Yakes 1 , Laura Shawver 1 , Ronan Le Moigne 1 , Daniel J. Anderson 1 , Mark Rolfe 1 , David Wustrow 1
Affiliation
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The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin–proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), 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-5083. 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 1 clinical trials in patients with multiple myeloma and solid tumors.
中文翻译：
发现了p97 AAA ATPase（CB-5083）的一流，有效，选择性和口服生物利用度抑制剂
AAA-ATPase p97在蛋白质稳态机制中起着至关重要的作用，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（ERAD）和自噬。在这里，我们描述了我们的主要优化工作，重点是体外效力，ADME和药物特性，这些特性导致发现了有效的，具有ATP竞争能力，D2选择性和口服生物利用度的p97抑制剂71 CB-5083。用71处理肿瘤细胞会导致标志物大量积累，与UPS和ERAD功能抑制相关，从而引起无法解决的蛋白毒性应激和细胞死亡。在荷瘤小鼠中，口服71在实体瘤和血液肿瘤的体内异种移植模型中，其引起未折叠蛋白反应（UPR）标记的快速积累，并随后诱导凋亡，导致持续的抗肿瘤活性。在多发性骨髓瘤和实体瘤患者中，有71项已进入1期临床试验。
更新日期：2015-12-04
中文翻译：
发现了p97 AAA ATPase（CB-5083）的一流，有效，选择性和口服生物利用度抑制剂
AAA-ATPase p97在蛋白质稳态机制中起着至关重要的作用，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（ERAD）和自噬。在这里，我们描述了我们的主要优化工作，重点是体外效力，ADME和药物特性，这些特性导致发现了有效的，具有ATP竞争能力，D2选择性和口服生物利用度的p97抑制剂71 CB-5083。用71处理肿瘤细胞会导致标志物大量积累，与UPS和ERAD功能抑制相关，从而引起无法解决的蛋白毒性应激和细胞死亡。在荷瘤小鼠中，口服71在实体瘤和血液肿瘤的体内异种移植模型中，其引起未折叠蛋白反应（UPR）标记的快速积累，并随后诱导凋亡，导致持续的抗肿瘤活性。在多发性骨髓瘤和实体瘤患者中，有71项已进入1期临床试验。
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