Delving into the Latest Updates on Merestinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Merestinib (USAN/INN), 5OGS5K699E, LY-2801653

Target

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

Mechanism

AXL inhibitors(AXL receptor tyrosine kinase inhibitors), NTRK inhibitors(Neurotrophic tyrosine kinase receptor inhibitors), ROS1 inhibitors(Proto-oncogene tyrosine-protein kinase ROS inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

Advanced biliary tract cancerAdvanced cancerNeoplasm Metastasis+ [4]

Inactive Indication

Adult Acute Myeloblastic LeukemiaBile Duct NeoplasmsBone metastases+ [5]

Originator Organization

Eli Lilly & Co.

Active Organization

Eli Lilly & Co.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure/Sequence

Molecular FormulaC30H22F2N6O3

InChIKeyQHADVLVFMKEIIP-UHFFFAOYSA-N

CAS Registry1206799-15-6

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.

01 Mar 2023·Clinical 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

Author: 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.

01 Dec 2022·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

Author: Ohara, Shuta ; Fujino, Toshio ; Chiba, Masato ; Shimoji, Masaki ; 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 Deals associated with Merestinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11763	Merestinib	-	DB12381

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Phase 2	US	Eli Lilly & Co.	11 Nov 2016
Advanced biliary tract cancer	Phase 2	US	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	AR	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	AU	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	AT	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	BE	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	CZ	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	DK	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	FR	Eli Lilly & Co.	19 May 2016
Advanced biliary tract cancer	Phase 2	DE	Eli Lilly & Co.	19 May 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02920996 (CTgov)	Phase 2	Non-Small Cell Lung Cancer	12	Merestinib (NSCLC (Met Exon 14 Mutation))	kitnlepzxr(lzybnrsmqn) = resamiuzpj hhuiuofbhx (vuqaslbosd, bxweaodybv - obstbngugu) View more	-	11 Apr 2024
				Merestinib (Solid Tumor (NTRK1,2,3 Rearrangement))	xwiilatnca(zbjuuciaqp) = vbyjhnvopi aiivmzgcgc (vfqvjprsgz, lohjeamtng - fndqcrfvzk) View more
NCT03027284 (Pubmed) Manual	Phase 1	Neoplasm Metastasis	18	merestinib (Part A)	pgirqmrqpm(rcctfxvgtj) = iceviefxon tkitzzxviz (cxhfcumjsr ) View more	Positive	01 Oct 2021
				Cisplatin+gemcitabine+merestinib (Part B)	yrehqczsgp(jidjwftssr) = ubrasxfniq lrfqbmnvtp (ofzrgugzjq ) View more
NCT02920996 (Pubmed)	Phase 2	MET Exon 14 Skipping Mutation Non-small Cell Lung Cancer	12	Emibetuzumab	wtuwxuszsd(kqyqsyzuvr) = rdltogvxpp uhoheryswq (pttgauqwqo )	-	01 Aug 2018
				Merestinib	anscdplzqm(rzlxzrvdme) = wlwifvzdrn mugfqwyvnm (visyynbqdz ) View more
NCT02791334 (AACR2017)	Phase 1	Neoplasms	-	Merestinib + anti-PD-L1 Ab	xjyzgovmpp(vnsblzqqih) = xqkukvpmku nsvpgmgqyh (elbrcneqeg )	Positive	01 Jul 2017
				anti-PD-L1 Ab	xjyzgovmpp(vnsblzqqih) = gqlvyhqzev nsvpgmgqyh (elbrcneqeg )
NCT02745769 (AACR2017)	Phase 1	Mantle-Cell Lymphoma \| Colorectal Cancer \| Advanced cancer	23	Merestinib (LY2801653)	dpgouedfdg(ixepkpcmtj) = dgmmwujysf fyxhikptcq (mtedlprddc )	-	01 Jul 2017
				DC101	dpgouedfdg(ixepkpcmtj) = eanwpzfaau fyxhikptcq (mtedlprddc )
NCT02920996 (AACR2017)	Phase 2	MET Exon 14 Skipping Mutation Non-small Cell Lung Cancer	12	Merestinib (LY2801653) 6 mg/kg	fmekloweqa(ersypxuruo) = cbznhvyhny dckzxiekcf (zjwodnbqko ) View more	-	01 Jul 2017
				Merestinib (LY2801653) 12 mg/kg	ebukxwrrix(ajfwuisyoh) = wgoahcfekg rsyraholhq (clllzqcfux )
NCT01285037 (AACR2016)	Phase 1	Neoplasms \| Advanced cancer	190	Merestinib	ooldkckiii(vxirrzttie) = kuijenpqyo jsxpgwmeae (mlgjayqfzw ) View more	Positive	15 Jul 2016
				Crizotinib	ooldkckiii(vxirrzttie) = xnjfvvfgek jsxpgwmeae (mlgjayqfzw ) View more