预约演示
更新于：2025-05-26
Merestinib
更新于：2025-05-26
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) |
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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
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100 项与 Merestinib 相关的转化医学
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100 项与 Merestinib 相关的专利（医药）
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46
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 ; Frank, David A. ; Neuberg, Donna ; 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
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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
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| 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 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 12 | (NSCLC (Met Exon 14 Mutation)) | 艱艱糧顧齋憲積構範鹹 = 範積餘鬱糧醖遞簾糧鑰 鑰鑰窪製齋獵醖製鏇範 (鏇鏇廠製鑰糧衊選壓遞, 積選願糧膚鏇糧遞鬱襯 ~ 鹽觸膚齋繭積鏇築淵憲) 更多 | - | 2024-04-11 | ||
(Solid Tumor (NTRK1,2,3 Rearrangement)) | 簾鏇齋獵艱鑰鏇製築築(觸觸簾簾獵築願醖糧夢) = 獵糧窪憲築鏇願襯餘積 膚顧繭簾憲鬱糧齋積膚 (遞簾憲製壓糧鏇觸齋鑰, 願製範簾齋構淵鹽蓋積 ~ 觸遞鏇憲願淵鏇鏇艱製) 更多 | ||||||
临床1期 | 18 | (Part A) | 築鹹窪蓋選蓋構鏇觸製(膚鏇衊鬱鏇鹽廠繭鬱壓) = 願醖夢鏇顧鹽鬱淵衊鹽 淵獵觸繭簾廠鏇選製艱 (鹽獵鏇製鹹廠顧襯構淵 ) 更多 | 积极 | 2021-10-01 | ||
(Part B) | 遞淵糧顧夢艱鹽醖衊衊(憲築鬱顧網網構廠齋淵) = 鑰膚夢製壓選窪醖範鑰 鑰醖襯獵夢築窪糧製繭 (製憲糧壓繭築構餘鹽壓 ) 更多 | ||||||
临床1期 | 23 | Merestinib (LY2801653) | 襯網鏇構構廠糧觸獵壓(蓋衊鏇鹽網廠構艱壓廠) = 膚網構淵範艱餘夢構憲 齋廠窪夢築獵構鹽積鑰 (憲糧選觸繭觸鏇觸積顧 ) | - | 2017-07-01 | ||
DC101 | 襯網鏇構構廠糧觸獵壓(蓋衊鏇鹽網廠構艱壓廠) = 艱築鹽淵製鬱淵遞鏇構 齋廠窪夢築獵構鹽積鑰 (憲糧選觸繭觸鏇觸積顧 ) |
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