Merestinib (LY2801653)
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MedKoo CAT#: 205526

CAS#: 1206799-15-6 (free base)

Description: Merestinib, also known as LY2801653, is an orally available, small molecule inhibitor of the proto-oncogene c-Met (mesenchymal-epithelial transition, also known as hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. c-Met inhibitor LY2801653 selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. This agent has potent anti-tumor efficacy in mono- and combination therapy in a broad range of cancers.

Chemical Structure

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Merestinib (LY2801653)
CAS# 1206799-15-6 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205526
Name: Merestinib (LY2801653)
CAS#: 1206799-15-6 (free base)
Chemical Formula: C30H22F2N6O3
Exact Mass: 552.17
Molecular Weight: 552.530
Elemental Analysis: C, 65.21; H, 4.01; F, 6.88; N, 15.21; O, 8.69

Price and Availability

Size Price Availability Quantity
10mg USD 150 Ready to ship
25mg USD 300 Ready to ship
50mg USD 500 Ready to ship
100mg USD 850 Ready to ship
200mg USD 1450 Ready to ship
500mg USD 2950 Ready to ship
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Related CAS #: 1206799-15-6 (free base)   1206801-37-7 (HCl)  

Synonym: LY-2801653; LY 2801653; LY2801653; Merestinib;

IUPAC/Chemical Name: N-(3-fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

InChi Key: QHADVLVFMKEIIP-UHFFFAOYSA-N

InChi Code: InChI=1S/C30H22F2N6O3/c1-17-3-9-23(30(40)38(17)22-7-4-20(31)5-8-22)29(39)36-21-6-10-27(25(32)12-21)41-28-11-18-16-35-37(2)26(18)13-24(28)19-14-33-34-15-19/h3-16H,1-2H3,(H,33,34)(H,36,39)

SMILES Code: O=C(C1=CC=C(C)N(C2=CC=C(F)C=C2)C1=O)NC3=CC=C(OC4=CC5=C(N(C)N=C5)C=C4C6=CNN=C6)C(F)=C3

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:   LY2801653 was identified and developed as a novel, potent, and orally active small molecule inhibitor of human c-Met. It demonstrated dose dependent inhibition of c-Met phosphorylation in xenograft tumors with a long lasting PD effect.  LY2801653 displayed potent anti-tumor efficacy in a number of non small cell lung, renal, pancreatic, and breast tumor models. Examination of c-Met expression in these tumors by immunohistochemistry (IHC) revealed a good correlation between response and c-Met expression in the tumor tissue.  LY2801653 treatment led to increase in functional vessel areas, and decrease in tumor hypoxia. Enhanced anti-tumor efficacy was achieved when Erlotinib was combined with LY2801653. . (source: http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/70/8_MeetingAbstracts/3611).   (source: http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/70/8_MeetingAbstracts/3611).            

Biological target: Merestinib (LY2801653) is a potent, c-Met inhibitor (Ki=2 nM) with anti-tumor activities and activity against MST1R (IC50=11 nM), FLT3 (IC50=7 nM), AXL (IC50=2 nM), MERTK (IC50=10 nM), TEK (IC50=63 nM), ROS1, DDR1/2 (IC50=0.1/7 nM) and MKNK1/2 (IC50=7 nM.
In vitro activity: To examine if merestinib inhibits NTRK1 phosphorylation in vitro, KM-12 cells were treated for 2 hours ranging in concentration from 3.9 -1000 nM. Merestinib showed a dose dependent decrease in p-NTRK1 Y490 resulting in complete inhibition at 62.5 nM as determined by western blot (Figure1B). Merestinib showed dose dependent inhibition of phosphorylated MAPK 42/44 (ERK) in concordance with their respective p-NTRK downstream signaling (Figure1B). Merestinib is a potent direct inhibitor of MKNK1/2, the kinases responsible for phosphorylating eIF4E at S209 [16]. In KM-12 cells, merestinib reduced p-eIF4E levels with near-complete inhibition at 62.5 nM (Figure1B). It was further examined if merestinib, M1 and M2 metabolites suppress KM-12 cell proliferation in vitro. Within 72 hours, treatment with merestinib, M1, or M2 suppressed cell proliferation with an IC50 of 10 nM, 16 nM and 102 nM, respectively. Collectively, these data suggest that merestinib and the metabolites M1 and M2 block both anchorage dependent and independent cell growth in TPM3-NTRK1 bearing KM-12 cells. Reference: Oncotarget. 2018 Mar 2; 9(17): 13796–13806. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862616/
In vivo activity: Merestinib (dosed once daily at 12 mg/kg or 24 mg/kg) (dosed twice daily at 30 mg/kg) was evaluated in mouse tumor models with NIH-3T3 cells expressing wild-type TPM3-NTRK1, TPM3-NTRK1 with G595R or G667C mutation. Merestinib treatment resulted in tumor regression in tumors expressing wild-type TPM3-NTRK1 (Figure6A). Similar extent of tumor regression was observed in both doses of merestinib treated cohorts in animals bearing tumors with the G667C mutant within 4 days of treatment initiation (12 mg/kg once daily, regression = 46.8%, p < 0.001; 24 mg/kg once daily, regression = 51.3%, p < 0.001) and maintained through the study period. Tumors expressing mutant G595R TPM3-NTRK1 insensitive to merestinib (T/C=65.2%, p=0.147) treatment (Figure (Figure 6C). Together, these data indicate that merestinib is a potent inhibitor of NTRK and blocks tumor progression in vivo in preclinical studies. Reference: Oncotarget. 2018 Mar 2; 9(17): 13796–13806. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862616/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 66.0 119.45

Preparing Stock Solutions

The following data is based on the product molecular weight 552.53 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Konicek BW, Capen AR, Credille KM, Ebert PJ, Falcon BL, Heady GL, Patel BKR, Peek VL, Stephens JR, Stewart JA, Stout SL, Timm DE, Um SL, Willard MD, Wulur IH, Zeng Y, Wang Y, Walgren RA, Betty Yan SC. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget. 2018 Feb 13;9(17):1379613806. doi: 10.18632/oncotarget.24488. PMID: 29568395; PMCID: PMC5862616. 2. Kosciuczuk EM, Saleiro D, Kroczynska B, Beauchamp EM, Eckerdt F, Blyth GT, Abedin SM, Giles FJ, Altman JK, Platanias LC. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016 Jul 21;128(3):410-4. doi: 10.1182/blood-2016-02-698704. Epub 2016 Jun 15. PMID: 27307295; PMCID: PMC4957163.
In vitro protocol: 1. Konicek BW, Capen AR, Credille KM, Ebert PJ, Falcon BL, Heady GL, Patel BKR, Peek VL, Stephens JR, Stewart JA, Stout SL, Timm DE, Um SL, Willard MD, Wulur IH, Zeng Y, Wang Y, Walgren RA, Betty Yan SC. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget. 2018 Feb 13;9(17):1379613806. doi: 10.18632/oncotarget.24488. PMID: 29568395; PMCID: PMC5862616. 2. Kosciuczuk EM, Saleiro D, Kroczynska B, Beauchamp EM, Eckerdt F, Blyth GT, Abedin SM, Giles FJ, Altman JK, Platanias LC. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016 Jul 21;128(3):410-4. doi: 10.1182/blood-2016-02-698704. Epub 2016 Jun 15. PMID: 27307295; PMCID: PMC4957163.
In vivo protocol: 1. Konicek BW, Capen AR, Credille KM, Ebert PJ, Falcon BL, Heady GL, Patel BKR, Peek VL, Stephens JR, Stewart JA, Stout SL, Timm DE, Um SL, Willard MD, Wulur IH, Zeng Y, Wang Y, Walgren RA, Betty Yan SC. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget. 2018 Feb 13;9(17):1379613806. doi: 10.18632/oncotarget.24488. PMID: 29568395; PMCID: PMC5862616. 2. Kosciuczuk EM, Saleiro D, Kroczynska B, Beauchamp EM, Eckerdt F, Blyth GT, Abedin SM, Giles FJ, Altman JK, Platanias LC. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016 Jul 21;128(3):410-4. doi: 10.1182/blood-2016-02-698704. Epub 2016 Jun 15. PMID: 27307295; PMCID: PMC4957163.

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1: Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL,  Wang Y, Wu W, Yan L, Yang WJ, Zhong B, Walgren RA. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and  other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2012 Dec 29. [Epub ahead of print] PubMed PMID: 23275061.