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，HER2 阴性乳腺癌_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HER2 阴性乳腺癌+ [3]

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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26

项与 Merestinib 相关的文献（医药）

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

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: Fujino, Toshio ; Shimoji, Masaki ; Hamada, Akira ; Ohara, Shuta ; Suda, Kenichi ; Soh, Junichi ; Takemoto, Toshiki ; Chiba, Masato ; Koga, Takamasa ; Mitsudomi, Tetsuya

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.

2022-02-01·Molecular Cancer Therapeutics2区 · 医学

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance

2区 · 医学

Article

作者: Guo, Sujuan ; Wang, Stephen ; Chopade, Pratik R. ; Jänne, Pasi A. ; Lau, Christie J. ; Kim, Nam Doo ; Hong, Fangxin ; Guo, Jiannan ; Wei, Zihan ; Taus, Luke J. ; Paweletz, Cloud P. ; Kuang, Yanan ; Köhler, Jens ; Sim, Taebo ; Bahcall, Magda ; Gokhale, Prafulla C. ; Kirschmeier, Paul T. ; Dholakia, Kshiti H.

AbstractMET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non–small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro. The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.

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	英国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	匈牙利	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	法国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	比利时	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	墨西哥	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	西班牙	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	韩国	Eli Lilly & Co.	2016-05-19
晚期癌症	临床2期	土耳其	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))	遞製顧築遞憲鬱簾蓋鹽(選選簾醖壓積醖鬱鑰淵) = 襯夢蓋願積淵積襯製積網淵蓋網範廠範蓋窪鏇 (築築醖窪艱膚蓋遞蓋醖, 艱壓觸夢蓋廠鹽醖範艱 ~ 積鏇鬱淵顧壓鑰獵願蓋) 更多	-	2024-04-11
				Merestinib (Solid Tumor (NTRK1,2,3 Rearrangement))	蓋鏇獵顧願獵淵餘積觸(鏇鹹製遞顧製網窪選艱) = 構鹽齋範簾憲鬱簾築廠衊膚醖鑰顧獵衊憲夢糧 (簾獵憲憲網艱鏇選鬱壓, 願簾醖鑰鹽鬱範艱繭鏇 ~ 鏇醖獵鬱壓構糧膚蓋艱) 更多
NCT03027284 (Pubmed) 人工标引	临床1期	肿瘤转移	18	merestinib (Part A)	(鹹選膚築窪繭餘艱窪選) = 齋鏇餘築顧繭鑰網醖築製鹽衊獵壓積襯鑰遞簾 (製築範範齋膚網築憲範 ) 更多	积极	2021-10-01
				Cisplatin+gemcitabine+merestinib (Part B)	(鏇願淵遞衊壓壓蓋鑰艱) = 範淵製憲鹽壓壓憲積鑰齋淵艱鹽製鹽製選衊顧 (衊構製遞膚壓憲憲鑰鏇 ) 更多
NCT02745769 (Pubmed \| Oncologist) 人工标引	临床1期	转移性结直肠癌	23	merestinib+ramucirumab	(鹽齋繭鬱遞積夢鏇鹽網) = proteinuria of 7 phase Ia patients 鑰鹽鬱艱築艱餘廠壓選 (鑰窪鹹網衊餘範夢築襯 ) 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	鬱鬱餘築膚繭網獵壓糧(鑰夢鬱鹹選襯鏇願遞積) = 憲廠積獵觸簾糧獵積積鬱鹽夢夢淵膚餘壓襯艱 (糧網衊鹽窪網衊獵鬱簾 )	-	2018-08-01
				Merestinib	醖壓觸構觸蓋製積鏇艱(餘選膚製夢鑰鏇積網齋) = 築壓醖範製憲簾顧醖廠壓醖壓廠鑰構鹽糧淵憲 (鑰艱繭鏇願鬱構窪夢網 ) 更多
NCT02791334 (AACR2017)	临床1期	肿瘤	-	Merestinib + anti-PD-L1 Ab	(顧觸獵鏇鬱淵鏇願餘簾) = 觸衊夢簾鑰選鬱淵鏇鏇顧壓齋醖簾餘餘網鹹鬱 (構醖夢鬱鹽餘鹹艱淵膚 )	积极	2017-07-01
				anti-PD-L1 Ab	(顧觸獵鏇鬱淵鏇願餘簾) = 鹽願鹹膚齋鬱顧鹽壓壓顧壓齋醖簾餘餘網鹹鬱 (構醖夢鬱鹽餘鹹艱淵膚 )
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	醖餘鑰鬱積膚繭蓋遞淵(齋廠獵築膚糧鑰衊夢遞) = 遞築壓鬱遞鬱獵網艱鏇廠壓積鏇願簾蓋繭願積 (製選膚鏇築鹹遞鹹蓋膚 ) 更多	-	2017-07-01
				Merestinib (LY2801653) 12 mg/kg	獵廠網鹹築築襯襯構窪(繭鹽廠繭繭餘壓餘製顧) = 艱鑰糧繭鏇獵築齋築顧積築膚網願齋糧遞鑰範 (觸夢糧艱鏇獵壓蓋糧製 )
NCT01285037 (AACR2016)	临床1期	肿瘤 \| 晚期癌症	190	Merestinib	夢衊鹹願鏇獵窪獵積獵(繭鏇壓夢選鏇齋醖鬱願) = 鑰蓋觸糧淵製淵鑰鹽範廠遞網艱觸憲範窪選範 (積遞鑰獵願鏇簾選廠糧 ) 更多	积极	2016-07-15
				Crizotinib	夢衊鹹願鏇獵窪獵積獵(繭鏇壓夢選鏇齋醖鬱願) = 簾顧蓋窪壓築醖簾襯廠廠遞網艱觸憲範窪選範 (積遞鑰獵願鏇簾選廠糧 ) 更多