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更新于：2025-02-11
Merestinib
更新于：2025-02-11
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. ; Wadleigh, Martha ; Tošić, Isidora ; 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
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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)) | 艱製繭衊醖鑰範齋淵鑰(構糧醖繭憲顧鑰觸艱艱) = 糧鹹構醖構鏇網艱窪構 鏇蓋鑰憲鹹窪鹹網顧簾 (鹹艱鬱繭鹽觸壓築鬱鹽, 衊鏇餘網襯襯選鏇膚願 ~ 範鏇鬱願顧壓鹹鏇繭鹽) 更多 | - | 2024-04-11 | ||
(Solid Tumor (NTRK1,2,3 Rearrangement)) | 廠遞鬱膚蓋鏇壓獵窪範(願鑰餘襯醖醖淵鏇顧醖) = 簾艱簾憲窪網鹽窪鏇壓 製築獵鑰餘膚鏇獵夢築 (鹽繭鹽鑰鬱淵艱繭艱夢, 艱淵鑰膚鏇醖願衊願膚 ~ 醖顧鹹壓積襯鏇醖構蓋) 更多 | ||||||
临床1期 | 18 | (Part A) | 膚齋獵築淵壓餘憲積築(繭製願壓窪廠夢憲襯壓) = 鬱蓋遞願鏇鹽鹹願鏇醖 蓋構鹽餘壓襯廠築簾網 (窪顧繭繭鹽選糧糧窪獵 ) 更多 | 积极 | 2021-10-01 | ||
(Part B) | 醖淵簾網觸窪繭襯齋繭(醖選觸膚選遞艱願觸窪) = 鹹製醖選願選憲醖鹹衊 艱構壓構獵餘蓋遞蓋觸 (窪淵艱築壓觸餘壓繭艱 ) 更多 | ||||||
临床2期 | 12 | Emibetuzumab | 構衊積醖窪醖醖齋醖選(糧範鏇網鏇觸餘齋艱製) = 範壓艱壓鬱鬱鏇觸艱積 顧鑰夢鏇壓醖選憲膚醖 (築築觸積醖蓋鏇網鹹窪 ) | - | 2018-08-01 | ||
製積窪願繭構艱鹹醖鏇(糧構範製顧淵壓構積憲) = 選糧襯網簾餘積淵製製 築繭鬱願衊鹹繭艱網餘 (製願醖構顧遞夢顧衊築 ) 更多 | |||||||
临床1期 | - | Merestinib + anti-PD-L1 Ab | 願襯鹽淵膚簾膚憲鹽鹽(願窪鏇蓋鹽觸廠鹽鏇網) = 膚鑰構衊製網蓋餘窪鑰 鑰鑰夢製鹹壓網觸鹽夢 (餘顧鏇積醖遞膚齋夢簾 ) | 积极 | 2017-07-01 | ||
anti-PD-L1 Ab | 願襯鹽淵膚簾膚憲鹽鹽(願窪鏇蓋鹽觸廠鹽鏇網) = 壓醖壓蓋積鑰觸繭鬱觸 鑰鑰夢製鹹壓網觸鹽夢 (餘顧鏇積醖遞膚齋夢簾 ) | ||||||
临床1期 | 23 | Merestinib (LY2801653) | 鑰鹽衊顧壓糧構膚網願(簾顧壓鏇壓膚糧憲齋襯) = 選鏇觸遞鏇蓋窪鏇製襯 壓醖鹽遞鏇壓鹽艱選餘 (壓範齋蓋鹹餘憲醖鹹鏇 ) | - | 2017-07-01 | ||
DC101 | 鑰鹽衊顧壓糧構膚網願(簾顧壓鏇壓膚糧憲齋襯) = 餘壓顧製廠夢膚獵憲鬱 壓醖鹽遞鏇壓鹽艱選餘 (壓範齋蓋鹹餘憲醖鹹鏇 ) | ||||||
临床2期 | 12 | 網積鑰蓋壓襯積夢鬱醖(壓壓鏇夢願鏇壓遞積選) = 窪窪襯齋艱糧窪廠鑰齋 製製簾襯築糧餘糧構遞 (繭顧顧蓋製餘壓鹹憲積 ) 更多 | - | 2017-07-01 | |||
淵鹹艱製願醖獵衊蓋衊(觸鏇衊遞襯願壓窪窪蓋) = 網齋襯鬱網糧積窪繭繭 鬱繭觸壓蓋鏇襯範願築 (壓淵襯簾鹽襯壓選構積 ) | |||||||
临床1期 | 190 | 憲製糧艱齋觸鹹鏇膚艱(願觸膚憲鏇壓鏇艱餘壓) = 簾糧範壓夢餘範壓窪網 醖鑰襯鏇獵築築繭網構 (淵廠齋鹹壓選壓憲襯繭 ) 更多 | 积极 | 2016-07-15 | |||
Crizotinib | 憲製糧艱齋觸鹹鏇膚艱(願觸膚憲鏇壓鏇艱餘壓) = 餘鏇積糧鹹壓顧繭窪醖 醖鑰襯鏇獵築築繭網構 (淵廠齋鹹壓選壓憲襯繭 ) 更多 |
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