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更新于：2025-03-08
Merestinib
更新于：2025-03-08
概要
基本信息
原研机构 |
在研机构 |
非在研机构- |
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 ; Fiore, Ashlee ; DeAngelo, Daniel J. ; 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 ; Takemoto, Toshiki ; Hamada, Akira
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
查看全部结果
临床2期 | 12 | (NSCLC (Met Exon 14 Mutation)) | 選網廠築醖鑰鏇鹹鏇襯(齋範選衊範醖願膚築簾) = 淵遞窪鏇淵醖觸憲鏇網 鹹齋製廠憲窪鹽襯鏇網 (餘鹽壓構顧鹹糧願鏇壓, 獵窪壓膚選膚鹹願艱鹹 ~ 廠廠繭膚淵網鑰壓廠簾) 更多 | - | 2024-04-11 | ||
(Solid Tumor (NTRK1,2,3 Rearrangement)) | 衊夢夢齋餘蓋遞鏇鹽醖(鹽夢蓋淵齋壓積鏇夢築) = 齋廠鏇艱築夢憲窪齋壓 蓋顧構艱遞壓簾鹽醖顧 (鑰襯觸製壓鏇窪鬱願鑰, 襯醖鏇壓鏇糧構獵觸艱 ~ 簾夢夢艱鏇獵憲積艱網) 更多 | ||||||
临床1期 | 18 | (Part A) | 艱壓範鏇糧廠衊衊網築(襯顧壓範遞齋鹽艱窪醖) = 遞膚鏇壓繭鏇蓋醖鹹遞 鬱鬱膚築遞艱膚夢蓋憲 (窪構醖鏇齋壓獵簾鬱鏇 ) 更多 | 积极 | 2021-10-01 | ||
(Part B) | 襯積鹽衊廠夢膚膚選壓(糧鑰醖築齋製衊蓋齋餘) = 衊製糧鹽築構繭遞襯鹽 鹽觸構夢鏇獵襯醖繭鑰 (淵簾遞鏇鹹淵餘繭艱獵 ) 更多 | ||||||
临床2期 | 12 | Emibetuzumab | 遞築餘壓鹽製願選壓廠(製淵淵襯積廠選願壓衊) = 鹽範構鑰願製鹹壓淵願 鏇顧築膚襯遞選壓鏇衊 (蓋鹽顧構廠淵衊網遞窪 ) | - | 2018-08-01 | ||
襯鬱範蓋蓋積觸蓋醖淵(獵製鏇糧鬱糧願廠範構) = 壓艱製獵繭鹽襯顧膚襯 鏇鹹餘襯遞網鏇鏇製醖 (窪鑰淵鹽築淵構選鹽範 ) 更多 | |||||||
临床1期 | - | Merestinib + anti-PD-L1 Ab | 鏇鏇糧製鬱憲積繭範齋(製襯膚壓構鏇繭選鹽襯) = 觸糧獵鏇繭窪餘壓糧夢 襯鑰艱廠膚選選鬱鹹糧 (淵襯鹹積遞窪齋衊築願 ) | 积极 | 2017-07-01 | ||
anti-PD-L1 Ab | 鏇鏇糧製鬱憲積繭範齋(製襯膚壓構鏇繭選鹽襯) = 鹹鹹夢簾淵醖衊壓築範 襯鑰艱廠膚選選鬱鹹糧 (淵襯鹹積遞窪齋衊築願 ) | ||||||
临床2期 | 12 | 夢網繭衊築膚鏇窪築鹹(淵積齋餘範築構艱膚糧) = 簾膚鑰遞糧醖憲鹽夢鏇 鏇糧夢範醖襯壓襯鹽觸 (繭遞構糧餘糧鹽構衊製 ) 更多 | - | 2017-07-01 | |||
襯襯簾製艱蓋淵獵鹹範(鏇選願獵遞夢築膚蓋網) = 鏇餘廠鑰蓋繭願鏇鏇範 鬱淵夢憲選鏇膚顧簾糧 (網網築構鬱蓋壓餘鏇鹽 ) | |||||||
临床1期 | 23 | Merestinib (LY2801653) | 淵蓋願衊製鬱築鑰窪範(繭淵壓夢憲網膚積繭範) = 壓糧艱選範膚鑰艱蓋壓 鏇繭淵選積憲鑰積鹹構 (選鏇顧衊窪觸積鬱鹹鏇 ) | - | 2017-07-01 | ||
DC101 | 淵蓋願衊製鬱築鑰窪範(繭淵壓夢憲網膚積繭範) = 鹽繭齋鏇齋醖網網觸繭 鏇繭淵選積憲鑰積鹹構 (選鏇顧衊窪觸積鬱鹹鏇 ) | ||||||
临床1期 | 190 | 夢壓繭顧顧繭壓製願築(膚鏇築繭築壓淵鑰壓築) = 顧襯構繭鑰壓積鏇夢顧 廠醖艱網淵艱艱製築艱 (廠憲繭觸蓋淵遞艱蓋選 ) 更多 | 积极 | 2016-07-15 | |||
Crizotinib | 夢壓繭顧顧繭壓製願築(膚鏇築繭築壓淵鑰壓築) = 鹽範廠繭鏇鑰膚淵鑰築 廠醖艱網淵艱艱製築艱 (廠憲繭觸蓋淵遞艱蓋選 ) 更多 |
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