预约演示
更新于：2025-05-16
Merestinib
更新于：2025-05-16
概要
基本信息
原研机构 |
在研机构 |
非在研机构- |
权益机构- |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评孤儿药 (美国) |
登录后查看时间轴
结构/序列
分子式C30H22F2N6O3 |
InChIKeyQHADVLVFMKEIIP-UHFFFAOYSA-N |
CAS号1206799-15-6 |
关联
11
项与 Merestinib 相关的临床试验NCT03292536
An Exploratory Phase 1B Study to Assess the Effects of Merestinib on Bone Metastases in Subjects With Breast Cancer
NCT03125239
A Phase 1 Study of Merestinib in Combination With LY2874455 in Relapsed or Refractory Acute Myeloid Leukemia
NCT03027284
A Phase I Study of Merestinib Monotherapy or in Combination With Other Anti-Cancer Agents in Japanese Patients With Advanced and/or Metastatic Cancer
100 项与 Merestinib 相关的临床结果
登录后查看更多信息
100 项与 Merestinib 相关的转化医学
登录后查看更多信息
100 项与 Merestinib 相关的专利（医药）
登录后查看更多信息
45
项与 Merestinib 相关的文献（医药）2025-03-01FREE RADICAL BIOLOGY AND MEDICINE
Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury
Article
作者: Luo, Yingli ; Luo, Xianyu ; Ma, Yinchu ; Liu, Didi ; Huang, Yi ; Zhou, Xinru ; Linghu, Maoyuan ; Huang, Qian ; Ji, Shurong ; Ru, Yi
The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases.
2023-03-01Clinical cancer research : an official journal of the American Association for Cancer Research
Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates
Article
作者: Stone, Richard M. ; Leonard, Rebecca ; Chen, Evan C. ; Tošić, Isidora ; Wadleigh, Martha ; Pozdnyakova, Olga ; Gandler, Helen ; Galinsky, Ilene ; DeAngelo, Daniel J. ; Fiore, Ashlee ; Neuberg, Donna ; Frank, David A. ; Garcia, Jacqueline S. ; Winer, Eric S. ; O'Day, Kelsey ; de Jonge, Adrienne ; Look, A. Thomas ; Fell, Geoffrey G. ; Luskin, Marlise R.
Abstract:
Purpose::
Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance.
Patients and Methods::
We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted.
Results::
The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.
Conclusions::
We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.
2022-12-01Journal of hematology & oncology
Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation
Article
作者: Ohara, Shuta ; Fujino, Toshio ; Shimoji, Masaki ; Chiba, Masato ; Koga, Takamasa ; Soh, Junichi ; Suda, Kenichi ; Mitsudomi, Tetsuya ; Hamada, Akira ; Takemoto, Toshiki
Abstract:
Background:
Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.
Methods:
The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs.
Results:
All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.
Conclusions:
The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.
100 项与 Merestinib 相关的药物交易
登录后查看更多信息
外链
| KEGG | Wiki | ATC | Drug Bank |
|---|---|---|---|
| D11763 | Merestinib | - |
研发状态
10 条进展最快的记录, 后查看更多信息
登录
| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 非小细胞肺癌 | 临床2期 | 美国 | 2016-11-11 | |
| 晚期胆道癌 | 临床2期 | 美国 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 阿根廷 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 澳大利亚 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 奥地利 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 比利时 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 捷克 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 丹麦 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 法国 | 2016-05-19 | |
| 晚期胆道癌 | 临床2期 | 德国 | 2016-05-19 |
登录后查看更多信息
临床结果
临床结果
适应症
分期
评价
查看全部结果
临床2期 | 12 | (NSCLC (Met Exon 14 Mutation)) | 齋衊鬱鬱衊鏇廠醖餘範 = 艱積蓋鏇築廠廠網廠鏇 鏇蓋蓋艱簾淵範選襯顧 (顧獵齋窪窪觸鏇製齋鬱, 選積選選夢製糧鏇醖顧 ~ 選構襯廠選醖築築膚壓) 更多 | - | 2024-04-11 | ||
(Solid Tumor (NTRK1,2,3 Rearrangement)) | 蓋選選艱選獵廠夢夢齋(襯築鬱糧觸遞網醖窪廠) = 窪遞鏇鑰構餘選網網壓 願積顧鏇網鹽顧製糧獵 (範鬱艱選醖鏇淵膚築構, 鹹簾艱膚構衊鏇簾鑰築 ~ 積製壓積衊壓鏇遞齋製) 更多 | ||||||
临床1期 | 18 | (Part A) | 鑰鏇衊齋簾選顧艱顧餘(簾餘構艱襯齋齋蓋艱夢) = 壓壓壓簾鏇願醖齋餘壓 簾齋餘鹹繭淵構製構鹽 (淵製範繭簾憲淵醖觸衊 ) 更多 | 积极 | 2021-10-01 | ||
(Part B) | 遞夢夢襯壓願選壓鑰獵(窪蓋憲顧廠夢淵鬱衊憲) = 構窪簾鏇鏇蓋膚廠蓋積 餘憲餘窪製糧顧膚醖積 (鏇糧顧遞糧鹽觸憲積鏇 ) 更多 | ||||||
临床1期 | 23 | Merestinib (LY2801653) | 選範積願積糧鑰鬱窪觸(襯積選積鹹鏇壓遞顧廠) = 顧蓋願觸淵鬱積範鏇簾 齋鹽鹹積餘窪夢餘鑰淵 (憲選築範衊鬱簾觸簾齋 ) | - | 2017-07-01 | ||
DC101 | 選範積願積糧鑰鬱窪觸(襯積選積鹹鏇壓遞顧廠) = 壓廠繭淵鏇獵夢繭選鹹 齋鹽鹹積餘窪夢餘鑰淵 (憲選築範衊鬱簾觸簾齋 ) |
登录后查看更多信息
转化医学
使用我们的转化医学数据加速您的研究。
登录
或
药物交易
使用我们的药物交易数据加速您的研究。
登录
或
核心专利
使用我们的核心专利数据促进您的研究。
登录
或
临床分析
紧跟全球注册中心的最新临床试验。
登录
或
批准
利用最新的监管批准信息加速您的研究。
登录
或
特殊审评
只需点击几下即可了解关键药物信息。
登录
或
Eureka LS:
全新生物医药AI Agent 覆盖科研全链路，让突破性发现快人一步
立即开始免费试用!
智慧芽新药情报库是智慧芽专为生命科学人士构建的基于AI的创新药情报平台，助您全方位提升您的研发与决策效率。
立即开始数据试用!
智慧芽新药库数据也通过智慧芽数据服务平台，以API或者数据包形式对外开放，助您更加充分利用智慧芽新药情报信息。
生物序列数据库
生物药研发创新
免费使用
化学结构数据库
小分子化药研发创新
免费使用