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Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties.
PLOS ONE ( IF 2.9 ) Pub Date : 2020-01-15 , DOI: 10.1371/journal.pone.0227727 Ravi K Anchoori 1, 2 , Marietta Tan 3 , Ssu-Hsueh Tseng 1 , Shiwen Peng 1 , Ruey-Shyang Soong 1 , Aliyah Algethami 1 , Palmer Foran 1 , Samarjit Das 1, 4 , Chenguang Wang 5 , Tian-Li Wang 1 , Hong Liang 1 , Chien-Fu Hung 1 , Richard B S Roden 1, 2, 6
PLOS ONE ( IF 2.9 ) Pub Date : 2020-01-15 , DOI: 10.1371/journal.pone.0227727 Ravi K Anchoori 1, 2 , Marietta Tan 3 , Ssu-Hsueh Tseng 1 , Shiwen Peng 1 , Ruey-Shyang Soong 1 , Aliyah Algethami 1 , Palmer Foran 1 , Samarjit Das 1, 4 , Chenguang Wang 5 , Tian-Li Wang 1 , Hong Liang 1 , Chien-Fu Hung 1 , Richard B S Roden 1, 2, 6
Affiliation
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We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome's 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael acceptor that adducts Cysteine 88 of RPN13. In probing the pharmacophore, we showed the benefit of the central nitrogen-bearing piperidone ring moiety compared to a cyclohexanone, the importance of the span of the aromatic wings from the central enone-piperidone ring, the contribution of both wings, and that substituents with stronger electron withdrawing groups were more cytotoxic. Potency was further enhanced by coupling of a second warhead to the central nitrogen-bearing piperidone as RA375 exhibited ten-fold greater activity against cancer lines than RA190, reflecting its nitro ring substituents and the addition of a chloroacetamide warhead. Treatment with RA375 caused a rapid and profound accumulation of high molecular weight polyubiquitinated proteins and reduced intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 was highly active against cell lines of multiple myeloma and diverse solid cancers, and demonstrated a wide therapeutic window against normal cells. For cervical and head and neck cancer cell lines, those associated with human papillomavirus were significantly more sensitive to RA375. While ARID1A-deficiency also enhanced sensitivity 4-fold, RA375 was active against all ovarian cancer cell lines tested. RA375 inhibited proteasome function in muscle for >72h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.
中文翻译：
具有抗肿瘤特性的候选小分子 RPN13 抑制剂的结构功能分析。
我们试图通过靶向蛋白酶体的 19S 调节颗粒内的泛素受体 RPN13 来设计对实体癌具有活性的泛素-蛋白酶体系统抑制剂。基于双苄基哌啶酮的原型抑制剂 RA190 是一种迈克尔受体，可与 RPN13 的半胱氨酸 88 加合物。在探索药效团时，我们展示了中心含氮哌啶酮环部分与环己酮相比的益处，芳香翼与中心烯酮哌啶酮环的跨度的重要性，两个翼的贡献，以及取代基更强的吸电子基团更具细胞毒性。通过将第二个弹头与中央含氮哌啶酮偶联进一步增强了效力，因为 RA375 对癌症细胞系的活性比 RA190 高 10 倍，反映其硝基环取代基和氯乙酰胺弹头的添加。RA375 治疗引起高分子量多泛素化蛋白的快速而深刻的积累，并降低细胞内谷胱甘肽水平，从而产生内质网和氧化应激，并引发细胞凋亡。RA375 对多发性骨髓瘤和多种实体癌的细胞系具有高度活性，并显示出对正常细胞的广泛治疗窗。对于宫颈癌细胞系和头颈部癌细胞系，与人乳头瘤病毒相关的细胞系对 RA375 的敏感性明显更高。虽然 ARID1A 缺陷也将敏感性提高了 4 倍，但 RA375 对所有测试的卵巢癌细胞系均具有活性。RA375 在对小鼠单次 ip 给药后抑制肌肉中的蛋白酶体功能超过 72 小时，
更新日期：2020-01-16
中文翻译：
具有抗肿瘤特性的候选小分子 RPN13 抑制剂的结构功能分析。
我们试图通过靶向蛋白酶体的 19S 调节颗粒内的泛素受体 RPN13 来设计对实体癌具有活性的泛素-蛋白酶体系统抑制剂。基于双苄基哌啶酮的原型抑制剂 RA190 是一种迈克尔受体，可与 RPN13 的半胱氨酸 88 加合物。在探索药效团时，我们展示了中心含氮哌啶酮环部分与环己酮相比的益处，芳香翼与中心烯酮哌啶酮环的跨度的重要性，两个翼的贡献，以及取代基更强的吸电子基团更具细胞毒性。通过将第二个弹头与中央含氮哌啶酮偶联进一步增强了效力，因为 RA375 对癌症细胞系的活性比 RA190 高 10 倍，反映其硝基环取代基和氯乙酰胺弹头的添加。RA375 治疗引起高分子量多泛素化蛋白的快速而深刻的积累，并降低细胞内谷胱甘肽水平，从而产生内质网和氧化应激，并引发细胞凋亡。RA375 对多发性骨髓瘤和多种实体癌的细胞系具有高度活性，并显示出对正常细胞的广泛治疗窗。对于宫颈癌细胞系和头颈部癌细胞系，与人乳头瘤病毒相关的细胞系对 RA375 的敏感性明显更高。虽然 ARID1A 缺陷也将敏感性提高了 4 倍，但 RA375 对所有测试的卵巢癌细胞系均具有活性。RA375 在对小鼠单次 ip 给药后抑制肌肉中的蛋白酶体功能超过 72 小时，
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