Merestinib

SKU: orb1223390

Description

LY2801653 is an orally available, small molecule inhibitor of the proto-oncogene c-Met (Ki: 2 nM) with potential antineoplastic activity. 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 the constitutively activated c-Met protein.(In Vitro):Merestinib (LY2801653) demonstrates effects on MET pathway-dependent cell scattering and cell proliferation. The mean IC50 value (n=6 determinations) of Merestinib (LY2801653) for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells is 35.2±6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells is 59.2 nM. Merestinib (LY2801653) also inhibits MST1R (IC50=11 nM), AXL (IC50=2 nM), MERTK (IC50=10 nM), TYRO3 (IC50=28 nM), ROS1, PDGFRA (IC50=41 nM), FLT3 (IC50=7 nM), TEK (IC50=63 nM), DDR1/2 (IC50=0.1/7 nM) and MKNK1/2 (IC50=7 nM).Transfection with the MET variants confers growth-factor independence and treatment with Merestinib (LY2801653) inhibits growth of these MET variant clones with an IC50 ranging from 3-fold more potent (V1092I) to approximately 6-fold less potent (L1195V) compare with the growth inhibition of cells with the MET wild-type sequence. Merestinib (LY2801653) (2, 5, and 10 μM) reduces the number of viable TFK-1 and SZ-1 cells in a dose and time dependent manner, and significant inhibits wound healing for TFK-1 and SZ-1 cell lines. Merestinib (LY2801653) inhibits cell invasion in TFK-1 and SZ-1 cells in a concentration dependent manner.\n(In Vivo):Merestinib (LY2801653) demonstrates anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. Merestinib (LY2801653) is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a pharmacodynamic residence time (Koff) of 0.00132 min-1 and t1/2 of 525 min. Merestinib (LY2801653) treatment inhibits MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 (90 % target inhibition dose) of 7.4 mg/kg. Merestinib (LY2801653) (20 mg/kg) reduces TFK-1 tumor growth significantly relative to vehicle control. Merestinib (LY2801653) inhibits the growth of intra- and extrahepatic CCC xenograft tumors.

Key Properties

• CAS Number: 1206799-15-6
• MW: 552.54
• Purity: >98% (HPLC)
• Formula: C₃₀H₂₂F₂N₆O₃
• SMILES: c1(=O)c(ccc(n1c1ccc(cc1)F)C)C(=O)Nc1cc(c(cc1)Oc1cc2cnn(c2cc1c1cn[nH]c1)C)F
• Target: Kinesin
• Solubility: DMSO : ≥ 32 mg/mL. 57.92 mM

Bioactivity

• In Vivo:
  Merestinib (LY2801653) demonstrates anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and In vivo vessel normalization effects. Merestinib (LY2801653) is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a pharmacodynamic residence time (Koff) of 0.00132 min-1 and t1/2 of 525 min. Merestinib (LY2801653) treatment inhibits MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 (90 % target inhibition dose) of 7.4 mg/kg. Merestinib (LY2801653) (20 mg/kg) reduces TFK-1 tumor growth significantly relative to vehicle control. Merestinib (LY2801653) inhibits the growth of intra-and extrahepatic CCC xenograft tumors.
• In Vitro:
  Merestinib (LY2801653) demonstrates effects on MET pathway-dependent cell scattering and cell proliferation. The mean IC50 value (n=6 determinations) of Merestinib (LY2801653) for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells is 35.2±6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells is 59.2 nM. Merestinib (LY2801653) also inhibits MST1R (IC50 = 11 nM), AXL (IC50 = 2 nM), MERTK (IC50 = 10 nM), TYRO3 (IC50 = 28 nM), ROS1, PDGFRA (IC50 = 41 nM), FLT3 (IC50 = 7 nM), TEK (IC50 = 63 nM), DDR1/2 (IC50 = 0.1/7 nM) and MKNK1/2 (IC50 = 7 nM). Transfection with the MET variants confers growth-factor independence and treatment with Merestinib (LY2801653) inhibits growth of these MET variant clones with an IC50 ranging from 3-fold more potent (V1092I) to approximately 6-fold less potent (L1195V) compare with the growth inhibition of cells with the MET wild-type sequence. Merestinib (LY2801653) (2, 5, and 10 μM) reduces the number of viable TFK-1 and SZ-1 cells in a dose and time dependent manner, and significant inhibits wound healing for TFK-1 and SZ-1 cell lines. Merestinib (LY2801653) inhibits cell invasion in TFK-1 and SZ-1 cells in a concentration dependent manner.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

LY2801653

Quick Database Links

Gene Symbol

Kinesin