ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.
ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.
复制标题
ONC201和丙烯酮：具有临床功效的抗癌化合物。
DOI：
10.1016/j.neo.2020.09.005
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Prabhu VV;Morrow S;Rahman Kawakibi A;Zhou L;Ralff M;Ray J;Jhaveri A;Ferrarini I;Lee Y;Parker C;Zhang Y;Borsuk R;Chang WI;Honeyman JN;Tavora F;Carneiro B;Raufi A;Huntington K;Carlsen L;Louie A;Safran H;Seyhan AA;Tarapore RS;Schalop L;Stogniew M;Allen JE;Oster W;El-Deiry WS
ONC201最初是作为肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导化合物TIC10被发现的。ONC201似乎作为G蛋白偶联受体（GPCR）多巴胺受体D2（DRD2）的选择性拮抗剂，以及线粒体蛋白酶酪蛋白裂解蛋白酶P（ClpP）的变构激动剂发挥作用。在靶点结合的下游，ONC201激活ATF4/CHOP介导的综合应激反应，导致TRAIL/死亡受体5（DR5）激活，通过c - myc抑制氧化磷酸化，并使肿瘤细胞中的Akt/ERK信号失活。这通常导致肿瘤细胞的DR5/TRAIL介导的凋亡；然而，也会出现不依赖DR5/TRAIL的凋亡、细胞周期阻滞或抗增殖作用。ONC201的作用不仅限于肿瘤主体细胞，还包括肿瘤微环境中的癌症干细胞、癌症相关成纤维细胞和免疫细胞，这些都有助于其疗效。ONC201可口服，能穿过完整的血脑屏障，目前正在晚期实体瘤和血液系统恶性肿瘤患者的临床试验中进行评估。ONC201在富含DRD2和/或ClpP表达的肿瘤类型中具有单药临床活性，包括高级别胶质瘤、子宫内膜癌、前列腺癌、套细胞淋巴瘤和肾上腺肿瘤的特定亚型。在临床前模型中已发现其与放疗、化疗、靶向治疗和免疫检查点药物具有协同作用，并且正在临床试验中进行评估。基于ONC201的核心药效团（称为吡咯并吡啶酮骨架）的构效关系揭示了正在研发的新型强效化合物。吡咯并吡啶酮代表了一种在肿瘤学中对以前无法成药的GPCR、ClpP和先天免疫途径进行治疗性靶向的新方法。
ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.
登录
查看更多内容
影响因子：
--
作者：
Arrillaga-Romany I;Chi AS;Allen JE;Oster W;Wen PY;Batchelor TT
通讯作者：
Batchelor TT
影响因子：
7.5
作者：
Aslostovar, Lili;Boyd, Allison L.;Bhatia, Mickie
通讯作者：
Bhatia, Mickie
鉴定径流诱导化合物突出了小分子ONC201/TIC10是一种激活步道途径的独特抗癌剂。
影响因子：
37.3
作者：
Allen JE;Krigsfeld G;Patel L;Mayes PA;Dicker DT;Wu GS;El-Deiry WS
通讯作者：
El-Deiry WS
影响因子：
4.6
作者：
Ames, E.;Hallett, W. H. D.;Murphy, W. J.
通讯作者：
Murphy, W. J.
影响因子：
3.9
作者：
Chi, Andrew S.;Tarapore, Rohinton S.;Mehta, Minesh P.
通讯作者：
Mehta, Minesh P.