LY2801653 (Merestinib) is a potent, orally bioavailable c-Met inhibitor (IC50=4.7nM; Ki value=2nM), with KD values of 20nM, 92nM, and 54nM for NTRK1, NTRK2, and NTRK3, respectively[1]. LY2801653 inhibits MET activity by stabilizing the inactive DFG-out conformation, suppresses MET-dependent tumor cell proliferation and migration/dissemination, and induces vascular normalization in xenograft tumors[2]. LY2801653 has been widely used to block Mnk kinase activity in acute myeloid leukemia cells and restrain leukemic progenitors[3].
In vitro, LY2801653 treatment for 72 hours significantly inhibited the viability of A549, H1703, and H1993 cells, with IC50 values of 627.6nM, 72.9nM, and 9.28nM, respectively[4]. Incubation of MET-overexpressing MKN45 cells with 50nM LY2801653 for 72 hours suppressed proliferation, accompanied by increased cleaved caspase-3 levels and decreased levels of Cyclin A2, Cyclin D1, and MCL-1[5]. 10µM of LY2801653 pretreatment for 1 hour effectively blocked the apoptosis induced by elesclomol-CuCl2 (ES-Cu) in HT-22 cells and reduced the level of reactive oxygen species (ROS)[6].
In vivo, LY2801653 treatment via oral administration at a dose of 12mg/kg daily for 5 weeks significantly inhibited tumor growth in the A549 xenograft mouse model[7]. Oral administration of LY2801653 at a dose of 12mg/kg/day for 21 consecutive days induced tumor regression in the Hs746t xenograft tumor model[8].
References:[1] Konicek B W, Capen A R, Credille K M, et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors[J]. Oncotarget, 2018, 9(17): 13796.
[2] Yan S B, Peek V L, Ajamie R, et al. 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[J]. Investigational new drugs, 2013, 31(4): 833-844.
[3] Kosciuczuk E M, Saleiro D, Kroczynska B, et al. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo[J]. Blood, The Journal of the American Society of Hematology, 2016, 128(3): 410-414.
[4] Kawada I, Hasina R, Arif Q, et al. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non–small cell lung cancer[J]. Cancer research, 2014, 74(3): 884-895.
[5] Zhu C, Shi H, Wu M, et al. A dual MET/AXL small‐molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment[J]. MedComm, 2020, 1(1): 103-118.
[6] Luo X, Linghu M, Zhou X, et al. Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury[J]. Free Radical Biology and Medicine, 2025, 229: 68-81.
[7] Wu W, Bi C, Credille K M, et al. Inhibition of tumor growth and metastasis in non–small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET[J]. Clinical Cancer Research, 2013, 19(20): 5699-5710.
[8] Yan S B, Um S L, Peek V L, et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping[J]. Investigational new drugs, 2018, 36(4): 536-544.