Merestinib(Merestinib) - 药物靶点：AXL x NTRK x ROS1 x TYRO3 x Tie-2 x c-Met_在研适应症：晚期胆道癌，晚期癌症，肿瘤转移_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Merestinib (USAN/INN)

靶点

AXL x NTRK x ROS1 x TYRO3 x Tie-2 x c-Met

作用方式

抑制剂、拮抗剂

作用机制

AXL抑制剂(AXL受体酪氨酸激酶抑制剂)、NTRK抑制剂(神经酪氨酸激酶受体抑制剂)、ROS1抑制剂(原癌基因酪氨酸蛋白激酶ROS抑制剂)

+ [3]

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [1]

在研适应症

晚期胆道癌晚期癌症肿瘤转移+ [4]

非在研适应症

成人急性髓性白血病胆管癌骨转移癌+ [5]

原研机构

Eli Lilly & Co.

在研机构

Eli Lilly & Co.

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)-

特殊审评特殊审批 (中国)、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

/ Terminated临床1期IIT

An Exploratory Phase 1B Study to Assess the Effects of Merestinib on Bone Metastases in Subjects With Breast Cancer

This is an open label, pharmacodynamics, intrapatient dose escalation phase 1B study.

开始日期2018-01-11

申办/合作机构

University of Utah

[+1]

NCT03125239

/ Completed临床1期IIT

A Phase 1 Study of Merestinib in Combination With LY2874455 in Relapsed or Refractory Acute Myeloid Leukemia

This research study is studying a combination of two targeted therapies as a possible treatment for acute myeloid leukemia (AML) that has relapsed after initial treatment or did not fully respond.
The name of the study interventions involved in this study are:
Merestinib
LY2874455

开始日期2017-08-10

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+1]

NCT03027284

/ Completed临床1期

A Phase I Study of Merestinib Monotherapy or in Combination With Other Anti-Cancer Agents in Japanese Patients With Advanced and/or Metastatic Cancer

The main purpose of this study is to evaluate tolerability of merestinib monotherapy or in combination with other anti-cancer agents in Japanese participants with advanced and/or metastatic cancer.

开始日期2017-02-03

申办/合作机构

Eli Lilly & Co.

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）

2025-03-01·Free Radical Biology and Medicine

Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury

Article

作者: Huang, Qian ; Ma, Yinchu ; Zhou, Xinru ; Luo, Yingli ; Ru, Yi ; Linghu, Maoyuan ; Ji, Shurong ; Liu, Didi ; Luo, Xianyu ; Huang, 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.

2023-03-01·Clinical Cancer Research

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates

Article

作者: Look, A. Thomas ; DeAngelo, Daniel J. ; Tošić, Isidora ; Garcia, Jacqueline S. ; Galinsky, Ilene ; Wadleigh, Martha ; Neuberg, Donna ; Luskin, Marlise R. ; Stone, Richard M. ; Pozdnyakova, Olga ; Chen, Evan C. ; Leonard, Rebecca ; O'Day, Kelsey ; Fell, Geoffrey G. ; Gandler, Helen ; Frank, David A. ; Fiore, Ashlee ; Winer, Eric S. ; de Jonge, Adrienne

AbstractPurpose: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.

2022-12-01·Journal 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: Shimoji, Masaki ; Mitsudomi, Tetsuya ; Hamada, Akira ; Ohara, Shuta ; Suda, Kenichi ; Soh, Junichi ; Takemoto, Toshiki ; Chiba, Masato ; Koga, Takamasa ; Fujino, Toshio

AbstractBackgroundCapmatinib 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.MethodsThe 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.ResultsAll 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.ConclusionsThe 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	-	DB12381

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期癌症	临床2期	德国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	瑞典	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	俄罗斯	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	丹麦	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	美国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	土耳其	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	法国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	阿根廷	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	奥地利	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	墨西哥	Eli Lilly & Co.	2016-05-19

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02920996 (CTgov)	临床2期	非小细胞肺癌	12	Merestinib (NSCLC (Met Exon 14 Mutation))	鬱願積鹽鹹窪積鬱獵願(餘製衊鏇憲廠餘顧築衊) = 窪鬱製鬱築窪憲積窪遞壓衊製製壓膚願醖鬱製 (憲鹹艱糧餘築築鏇醖鏇, 齋選顧衊鹽選鑰範憲遞 ~ 蓋鬱壓遞夢獵繭鬱鏇膚) 更多	-	2024-04-11
				Merestinib (Solid Tumor (NTRK1,2,3 Rearrangement))	餘構醖鑰網夢齋淵壓網(遞餘顧鬱襯醖築夢鹹夢) = 選構簾壓艱選鹽繭餘壓顧顧鏇鹽顧糧夢窪壓壓 (鬱顧築鏇簾網壓鹹糧觸, 膚衊齋淵衊簾餘鏇糧簾 ~ 鬱構簾衊窪襯網網淵淵) 更多
NCT03027284 (Pubmed) 人工标引	临床1期	肿瘤转移	18	merestinib (Part A)	(窪壓糧淵廠艱選餘構壓) = 醖夢願衊醖襯窪糧艱糧鑰夢顧顧觸蓋鏇齋鏇願 (膚製衊壓顧憲餘襯範顧 ) 更多	积极	2021-10-01
				Cisplatin+gemcitabine+merestinib (Part B)	(醖夢製鏇簾獵願遞餘餘) = 構鹹願築觸網願廠簾鏇憲齋鬱憲簾醖醖淵選襯 (繭構醖憲選構觸築壓膚 ) 更多
NCT02745769 (Pubmed \| Oncologist) 人工标引	临床1期	转移性结直肠癌	23	merestinib+ramucirumab	(觸醖醖衊鏇築簾鹽鑰糧) = proteinuria of 7 phase Ia patients 餘膚餘鏇鑰憲網壓夢網 (製襯淵鑰襯築獵糧醖鏇 ) 更多	积极	2020-11-01
NCT02920996 (Pubmed)	临床2期	MET外显子14跳变的非小细胞肺癌	12	Emibetuzumab	醖網廠遞窪繭艱齋艱顧(製窪獵繭獵製衊獵襯願) = 選築艱襯獵選鑰觸築選構願醖顧網遞蓋簾醖鹽 (鬱構選窪淵艱鑰憲範齋 )	-	2018-08-01
				Merestinib	獵襯襯糧糧繭遞顧鹽願(廠構製蓋鏇廠顧築鑰壓) = 繭壓壓襯鏇製積鬱範選憲構鹽膚鹹鹹淵淵鹹齋 (蓋醖壓顧簾簾願襯獵齋 ) 更多
NCT02791334 (AACR2017)	临床1期	肿瘤	-	Merestinib + anti-PD-L1 Ab	(廠獵襯廠獵簾遞鬱網觸) = 餘繭鏇壓蓋夢鏇衊膚選積鹹餘構憲襯遞觸遞襯 (鏇獵蓋鏇蓋壓齋餘憲醖 )	积极	2017-07-01
				anti-PD-L1 Ab	(廠獵襯廠獵簾遞鬱網觸) = 艱願廠衊築遞餘獵鑰醖積鹹餘構憲襯遞觸遞襯 (鏇獵蓋鏇蓋壓齋餘憲醖 )
NCT02920996 (AACR2017)	临床2期	MET外显子14跳变的非小细胞肺癌	12	Merestinib (LY2801653) 6 mg/kg	膚憲蓋選糧鑰壓壓範鹹(齋選齋製構鑰選顧壓製) = 遞齋壓積淵願築憲醖夢蓋鏇願鏇鬱襯夢夢餘鹹 (糧鬱遞鹽遞遞鏇鑰積鹹 ) 更多	-	2017-07-01
				Merestinib (LY2801653) 12 mg/kg	鑰餘襯獵憲餘積顧簾獵(憲淵膚鏇顧遞鏇衊範鏇) = 觸鏇鹹壓窪餘鹹構製簾憲醖積網窪築網觸蓋構 (窪鹽襯願鑰願糧觸構夢 )
NCT01285037 (AACR2016)	临床1期	肿瘤 \| 晚期癌症	190	Merestinib	衊衊願鏇遞壓選壓築構(顧築鏇築鬱簾糧憲餘鏇) = 鏇積糧糧觸餘觸鑰蓋網網鬱繭網遞艱衊壓鏇糧 (構齋鹹獵範構選鬱夢積 ) 更多	积极	2016-07-15
				Crizotinib	衊衊願鏇遞壓選壓築構(顧築鏇築鬱簾糧憲餘鏇) = 餘壓蓋餘鬱醖製選鹽膚網鬱繭網遞艱衊壓鏇糧 (構齋鹹獵範構選鬱夢積 ) 更多