Discovery and clinical introduction of first-in-class imipridone ONC201.
Discovery and clinical introduction of first-in-class imipridone ONC201.
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DOI：
10.18632/oncotarget.11814
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发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
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作者：
Allen JE;Kline CL;Prabhu VV;Wagner J;Ishizawa J;Madhukar N;Lev A;Baumeister M;Zhou L;Lulla A;Stogniew M;Schalop L;Benes C;Kaufman HL;Pottorf RS;Nallaganchu BR;Olson GL;Al-Mulla F;Duvic M;Wu GS;Dicker DT;Talekar MK;Lim B;Elemento O;Oster W;Bertino J;Flaherty K;Wang ML;Borthakur G;Andreeff M;Stein M;El-Deiry WS
ONC201是一种新型抗癌化合物吡普利酮的创始成员，该化合物目前正在多种晚期癌症的II期临床试验中。自从发现ONC201是一种不依赖p53的TRAIL基因转录诱导剂以来，临床前研究已经确定，ONC201对多种肿瘤细胞具有抗增殖和促凋亡作用，但对正常细胞没有作用。ONC201的作用机制包括参与不依赖于perk的综合应激反应的激活，导致DR5的肿瘤上调和Akt/ERK双失活，随后Foxo3a的激活导致死亡配体TRAIL的上调。ONC201在动物模型中具有口服活性，给药频率不高，可产生持续的药效学效应，且无遗传毒性。ONC201治疗晚期侵袭性难治性实体瘤的首次人体临床试验证实，ONC201具有异常良好的耐受性，并确定了推荐的II期剂量为625 mg，每三周口服一次，与临床前模型的有效水平相当。临床试验正在评估ONC201在多种实体瘤和血液系统恶性肿瘤中的单药疗效，并探索替代给药方案。此外，在其他肿瘤适应症中显示出前景的化学类似物正在临床前开发中。总之，由ONC201及其化学类似物组成的丙咪酮家族代表了一类新的抗癌疗法，其独特的作用机制正在进行临床试验。
ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.