An inhibitor of oxidative phosphorylation exploits cancer vulnerability.,Nature Medicine

当前位置： X-MOL 学术 › Nat. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

An inhibitor of oxidative phosphorylation exploits cancer vulnerability.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-06-11 , DOI: 10.1038/s41591-018-0052-4
Jennifer R Molina _{1,

2} , Yuting Sun _{1,

2} , Marina Protopopova _{1,

2} , Sonal Gera _{1,

2} , Madhavi Bandi _{1,

2} , Christopher Bristow _{1,

2} , Timothy McAfoos ₁ , Pietro Morlacchi _{1,

3} , Jeffrey Ackroyd ₄ , Ahmed-Noor A Agip ₅ , Gheath Al-Atrash ₆ , John Asara ₇ , Jennifer Bardenhagen ₁ , Caroline C Carrillo ₈ , Christopher Carroll ₁ , Edward Chang _{1,

2} , Stefan Ciurea ₆ , Jason B Cross ₁ , Barbara Czako ₁ , Angela Deem _{1,

2} , Naval Daver ₉ , John Frederick de Groot ₈ , Jian-Wen Dong ₈ , Ningping Feng _{1,

2} , Guang Gao _{1,

2} , Jason Gay _{1,

2} , Mary Geck Do ₁ , Jennifer Greer ₁ , Virginia Giuliani _{1,

2} , Jing Han _{1,

2} , Lina Han ₉ , Verlene K Henry ₈ , Judy Hirst ₅ , Sha Huang ₁ , Yongying Jiang ₁ , Zhijun Kang ₁ , Tin Khor _{1,

2} , Sergej Konoplev ₁₀ , Yu-Hsi Lin ₄ , Gang Liu ₁ , Alessia Lodi ₁₁ , Timothy Lofton ₁ , Helen Ma ₉ , Mikhila Mahendra _{1,

2} , Polina Matre ₉ , Robert Mullinax _{1,

2} , Michael Peoples _{1,

2} , Alessia Petrocchi ₁ , Jaime Rodriguez-Canale ₁₂ , Riccardo Serreli ₅ , Thomas Shi _{1,

2} , Melinda Smith _{1,

2} , Yoko Tabe _{9,

13} , Jay Theroff ₁ , Stefano Tiziani ₁₁ , Quanyun Xu ₁ , Qi Zhang ₉ , Florian Muller ₄ , Ronald A DePinho ₁₄ , Carlo Toniatti _{1,

2} , Giulio F Draetta _{1,

2,

15} , Timothy P Heffernan _{1,

2} , Marina Konopleva ₉ , Philip Jones ₁ , M Emilia Di Francesco ₁ , Joseph R Marszalek _{1,

2}

Affiliation

Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Agilent Technologies Inc., Lexington, MA, USA.
Department of Cancer Imaging Systems, University of Texas MD Cancer Center, Houston, TX, USA.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, UK.
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Next Generation Hematology Laboratory Medicine, Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

中文翻译：

氧化磷酸化的抑制剂利用了癌症的脆弱性。

代谢重编程是肿瘤生物学的新兴标志，也是肿瘤药物发现中积极追求的机会。广泛的努力集中在糖酵解的治疗目标上，而药物线粒体氧化磷酸化（OXPHOS）仍未开发，部分原因是对OXPHOS至关重要的肿瘤情况的不完全了解。在这里，我们报告了IACS-010759的发现，IACS-010759是线粒体电子传输链复合体I的临床级小分子抑制剂。在依赖于OXPHOS的脑癌和急性髓细胞白血病（AML）模型中，用IACS-010759处理可强烈抑制增殖并诱导凋亡，这可能是由于能量消耗和天冬氨酸产生减少的组合，导致核苷酸生物合成受损。在脑癌和AML模型中，在IACS-010759治疗后，以良好的耐受剂量在体内有效地抑制了肿瘤的生长。IACS-010759目前正在针对复发/难治性AML和实体瘤的1期临床试验中进行评估。

更新日期：2018-06-12

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>