Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor.
Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor.
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DOI：
10.1371/journal.pone.0285221
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
Roden, Richard B. S.
中科院分区：
文献类型：
--
作者：
Anchoori, Ravi K.;Anchoori, Vidyasagar;Lam, Brandon;Tseng, Ssu-Hsueh;Das, Samarjit;Velasquez, Fernanda Carrizo;Karanam, Balasubramanyam;Poddatoori, Deepika;Patnam, Ramesh;Rudek, Michelle A.;Chang, Yung-Nien;Roden, Richard B. S.
硼替佐米在治疗多发性骨髓瘤方面取得了成功，但对实体瘤无效，且其导致的神经病变、血小板减少等毒性以及耐药性的出现，促使人们努力寻找替代的蛋白酶体抑制剂。双亚苄基哌啶酮类化合物（如RA190）可与ADRM1/RPN13共价结合，ADRM1/RPN13是一种泛素受体，有助于识别蛋白酶体的多聚泛素化底物，随后对其进行去泛素化和降解。虽然这些候选的RPN13抑制剂（iRPN13）在癌症小鼠模型中显示出有前景的抗癌活性，但它们的类药性质并不理想。在此，我们介绍Up284，这是一种新型候选iRPN13，其中心为螺碳环，取代了RA190存在问题的哌啶酮核心。源自多种癌症类型（卵巢癌、三阴性乳腺癌、结肠癌、宫颈癌、前列腺癌、多发性骨髓瘤和胶质母细胞瘤）的细胞系对Up284敏感，包括几种对硼替佐米或顺铂耐药的细胞系。Up284和顺铂在体外显示出协同细胞毒性。Up284诱导的细胞毒性与线粒体功能障碍、活性氧水平升高、极高分子量的多聚泛素化蛋白聚集体积累、未折叠蛋白反应以及早期细胞凋亡有关。Up284和RA190（而非硼替佐米）在体外可增强抗原呈递。Up284在数小时内从血浆中清除，并在24小时内积聚在主要器官中。给小鼠腹腔注射或口服单剂量的Up284，可抑制肌肉和肿瘤中的蛋白酶体功能超过48小时。在重复给药研究中，小鼠对Up284耐受性良好。Up284在卵巢癌的异种移植、同基因和基因工程小鼠模型中均显示出治疗活性。
Bortezomib has been successful for treatment of multiple myeloma, but not against solid tumors, and toxicities of neuropathy, thrombocytopenia and the emergence of resistance have triggered efforts to find alternative proteasome inhibitors. Bis-benzylidine piperidones such as RA190 covalently bind ADRM1/RPN13, a ubiquitin receptor that supports recognition of polyubiquitinated substrates of the proteasome and their subsequent deububiqutination and degradation. While these candidate RPN13 inhibitors (iRPN13) show promising anticancer activity in mouse models of cancer, they have suboptimal drug-like properties. Here we describe Up284, a novel candidate iRPN13 possessing a central spiro-carbon ring in place of RA190’s problematic piperidone core. Cell lines derived from diverse cancer types (ovarian, triple negative breast, colon, cervical and prostate cancers, multiple myeloma and glioblastoma) were sensitive to Up284, including several lines resistant to bortezomib or cisplatin. Up284 and cisplatin showed synergistic cytotoxicity in vitro. Up284-induced cytotoxicity was associated with mitochondrial dysfunction, elevated levels of reactive oxygen species, accumulation of very high molecular weight polyubiquitinated protein aggregates, an unfolded protein response and the early onset of apoptosis. Up284 and RA190, but not bortezomib, enhanced antigen presentation in vitro. Up284 cleared from plasma in a few hours and accumulated in major organs by 24 h. A single dose of Up284, when administered to mice intra peritoneally or orally, inhibited proteasome function in both muscle and tumor for >48 h. Up284 was well tolerated by mice in repeat dose studies. Up284 demonstrated therapeutic activity in xenograft, syngeneic and genetically-engineered murine models of ovarian cancer.
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影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
影响因子：
50.3
作者：
Anchoori RK;Karanam B;Peng S;Wang JW;Jiang R;Tanno T;Orlowski RZ;Matsui W;Zhao M;Rudek MA;Hung CF;Chen X;Walters KJ;Roden RB
通讯作者：
Roden RB
DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
3.7
作者：
Fejzo, Marlena S.;Anderson, Lee;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
影响因子：
3.7
作者：
Fejzo, Marlena S.;Dering, Judy;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.