Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

医学 耐受性 药理学 临床试验 髓系白血病 组蛋白脱乙酰酶抑制剂 临床终点 神经毒性 肿瘤科 毒性 内科学 不利影响 组蛋白脱乙酰基酶 组蛋白 化学 基因 生物化学
作者
Timothy A. Yap,Naval Daver,Mikhila Mahendra,Jixiang Zhang,Carlos Kamiya-Matsuoka,Funda Meric‐Bernstam,Hagop M. Kantarjian,Farhad Ravandi,Meghan Collins,Maria Emilia Di Francesco,Ecaterina E. Dumbrava,Siqing Fu,Sisi Gao,Jason Gay,Sonal Gera,Jing Han,David S. Hong,Elias Jabbour,Zhenlin Ju,Daniel D. Karp,Alessia Lodi,Jennifer R. Molina,Natalia Baran,Aung Naing,Maro Ohanian,Shubham Pant,Naveen Pemmaraju,Prithviraj Bose,Sarina A. Piha‐Paul,Jordi Rodón,Carolina Salguero,Koji Sasaki,Anand Kumar Singh,Vivek Subbiah,Apostolia M. Tsimberidou,Quanyun A. Xu,Musa Yılmaz,Qi Zhang,Yuan Li,Christopher A. Bristow,Meenakshi B. Bhattacharjee,Stefano Tiziani,Timothy P. Heffernan,Christopher P. Vellano,Philip Jones,Cobi J. Heijnen,Annemieke Kavelaars,Joseph R. Marszalek,Marina Konopleva
出处
期刊:Nature Medicine [Springer Nature]
卷期号:29 (1): 115-126 被引量:131
标识
DOI:10.1038/s41591-022-02103-8
摘要

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
打打应助枯木逢春采纳,获得10
刚刚
1秒前
韩涵完成签到 ,获得积分10
1秒前
无花果应助ccccchen采纳,获得10
1秒前
a雪橙完成签到 ,获得积分10
2秒前
酷波er应助xuxuxu采纳,获得10
2秒前
孤独的AD钙完成签到,获得积分10
2秒前
罗_应助俭朴的皮卡丘采纳,获得10
2秒前
睿睿斌斌完成签到,获得积分10
3秒前
3秒前
Islet完成签到,获得积分10
3秒前
xxxx发布了新的文献求助10
3秒前
btyjs完成签到,获得积分10
3秒前
chenchen完成签到,获得积分10
3秒前
俗丨完成签到,获得积分10
4秒前
共享精神应助大方百招采纳,获得10
4秒前
5秒前
雪白秋柔完成签到 ,获得积分10
5秒前
zhongzihao完成签到,获得积分10
5秒前
米兰的小铁匠完成签到 ,获得积分10
6秒前
Islet发布了新的文献求助10
6秒前
lcx完成签到,获得积分10
6秒前
7秒前
8秒前
cici发布了新的文献求助10
8秒前
8秒前
吃饭饭发布了新的文献求助10
9秒前
Silole完成签到,获得积分10
10秒前
10秒前
meng发布了新的文献求助10
10秒前
NuyaoH完成签到,获得积分10
11秒前
丘比特应助miemie66采纳,获得10
11秒前
12秒前
13秒前
13秒前
科研通AI2S应助Islet采纳,获得10
13秒前
Ava应助丰富的不惜采纳,获得10
13秒前
微笑念薇完成签到 ,获得积分10
14秒前
woo完成签到,获得积分10
15秒前
chen0815发布了新的文献求助10
15秒前
高分求助中
The ACS Guide to Scholarly Communication 2500
Microlepidoptera Palaearctica, Volumes 1 and 3 - 13 (12-Volume Set) [German] 1122
The Data Economy: Tools and Applications 1000
Diamonds: Properties, Synthesis and Applications 800
PraxisRatgeber Mantiden., faszinierende Lauerjäger. – Buch gebraucht kaufen 700
Mantiden - Faszinierende Lauerjäger – Buch gebraucht kaufen 700
Ожившие листья и блуждающие цветы. Практическое руководство по содержанию богомолов [Alive leaves and wandering flowers. A practical guide for keeping praying mantises] 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3095943
求助须知:如何正确求助?哪些是违规求助? 2747836
关于积分的说明 7596995
捐赠科研通 2399476
什么是DOI,文献DOI怎么找? 1273093
科研通“疑难数据库(出版商)”最低求助积分说明 615534
版权声明 598948