Reactome | Anti-MET small tyrosine kinase inhibitors bind MET

Anti-MET small tyrosine kinase inhibitors bind MET

Stable Identifier

R-HSA-9735946

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Anti-MET small tyrosine kinase inhibitors bind MET

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Several tyrosine kinase inhibitors (TKIs) have MET as their primary target. The majority of these TKIs act by competing with ATP for binding to the ATP binding pocket in the catalytic cleft of MET, thus inhibiting HGF-induced trans autophosphorylation and activation of MET homodimers, but some do not compete with ATP binding and instead act as allosteric inhibitors. In addition, several TKIs designed for other tyrosine kinases bind MET as their non primary target (reviewed in Comoglio et al. 2018).

TKIs whose primary target is MET are:
AMG-337: an ATP competitive inhibitor, highly specific for MET (Hughes et al. 2016);
amuvatinib (also known as MP470): an ATP competitive inhibitor of MET, KIT and AXL (Mahadevan et al. 2007); inhibits MET trans-autophosphorylation in response to HGF stimulation (Phillip et al. 2013); annotated as a candidate MET inhibitor due to insufficient availability of experimental data;
BMS-777607: an ATP competitive MET inhibitor (Schroeder et al. 2009); also inhibits MST1R (also known as RON) (Zeng et al. 2014);
cabozantinib (also known as XL184): an ATP comptetitive inhibitor of MET, KDR, KIT, RET, AXL, TEK and FLT3 (Yakes et al. 2011), acts by inhibiting trans-autophosphorylation of MET (Yakes et al. 2011, Xiang et al. 2014), thus interfering with HGF induced cell migration (Yakes et al. 2011); can increase the efficacy of other anti cancer drugs by inhibiting the action of the ATP dependent xenobiotic transporter ABCG2 (Zhang et al. 2017);
capmatinib (also known as IN280): an ATP competitive reversible inhibitor of MET (Liu et al. 2011);
crizotinib (also known as PF-2341066): an ATP competitive MET inhibitor (Zou et al. 2007)
foretinib (also known as XL2880 and GSK1363089): an ATP competitive inhibitor of MET; also inhibits KDR, KIT, MST1R, FLT1, FLT4, AXL and TEK (Qian et al. 2009, Kataoka et al. 2012);
glesatinib (also known as MGCD265): does not compete with ATP, but inhibits HGF dependent MET trans-autophosphorylation; is effective against MET exon 14 mutants that are resistant to ATP competitive inhibitors (Engstrom et al. 2017);
golvatinib (also known as E7050): a dual inhibitor of MET and KDR (Nakagawa et al. 2010)
MK-2461: an ATP competitive MET inhibitor; does not prevent HGF induced trans-autophosphorylation of the MET kinase activation loop, but prevents trans-autophosphorylation of the juxtamembrane domain and C terminal docking sites of MET (Pan et al. 2010); besides inhibiting MET, MK-2461 shows a similar potency against MST1R (RON) and FLT1 receptor tyrosine kinases (RTKs), and 8- to 30-fold lower potency against RTKs FGFR1, FGFR2, FGFR3, PDGFRB, KDR, FLT3, FLT4, NTRK1 (TRKA) and NTRK2 (TRKB);
OMO-1, annotated as a candidate due to insufficient published evidence; OMO-1 is an ATP competitive MET inhibitor (Libouban et al. 2018 - conference abstract, no data shown) that interferes with MET trans-autophosphorylation in response to HGF stimulation (Steenbrugge et al. 2021);
PHA-665752: an ATP competitive inhibitor of MET, inhibits HGF induced trans-autophosphorylation of MET and downstream cell proliferation and motility (Christensen et al. 2003);
savolitinib (also known as volitinib or AZD6094): an ATP competitive MET inhibitor (Jia et al. 2014, Gavine et al. 2015);
SGX-523: an ATP competitive, highly selective MET inhibitor; stabilizes MET in a unique inactive conformation, inaccessible to other protein kinases; abrogates HGF induced MET trans-autophosphorylation (Buchanan et al. 2009);
SU11274: an ATP competitive, selective MET inhibitor (50 times higher affinity for MET than other tested RTKs) (Sattler et al. 2003);
tepotinib: an ATP competitive MET inhibitor (Zhang et al. 2019);
tivantinib (also known as ARQ-197) is annotated as a candidate MET inhibitor because of contradicting evidence; it was initially found that tivantinib does not compete with ATP and acts as an allosteric inhibitor, diminishing trans-autophosphorylation of ligand-activated MET dimers (Munshi et al. 2010), but this could not be reproduced by Basilico et al. 2013; the study by Basilico et al. 2013. indicated that tivantinib displays a nonspecific, MET-independent cytotoxic effect by perturbing microtubule dynamics (Basilico et al. 2013); tivantinib is subject to multi drug resistance-related export via ATP-dependent xenobiotic transporter ABCG2 (Wu et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
23532890	Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET Pennacchietti, S, Serini, G, Valdembri, D, Michieli, P, Vigna, E, Arena, S, Chiriaco, C, Basilico, C, Bardelli, A	Clin Cancer Res	2013
19260711	Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily Schmidt, RJ, Henley, B, Kamath, A, Lippy, J, Schroeder, GM, Jeyaseelan, R, Zhang, Y, Tokarski, JS, Kim, K, Zhang, Y, Wei, D, Clark, C, Dai, J, An, Y, Trainor, GL, Wautlet, BS, Chen, XT, Sack, JS, Fargnoli, J, Stefanski, K, Oppenheimer, S, Shen, G, Gullo-Brown, J, Manne, V, Lombardo, LJ, Cornelius, LA, Hunt, JT, Borzilleri, RM, Gupta, A, Cai, ZW, Williams, DK	J Med Chem	2009
14500382	A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase Liang, C, Quinnan, LA, Salgia, R, Ma, P, Shirazian, S, Podar, K, Chu, SC, Pride, YB, Gramlich, JL, Sattler, M, Christensen, JG	Cancer Res	2003
33731699	OMO-1 reduces progression and enhances cisplatin efficacy in a 4T1-based non-c-MET addicted intraductal mouse model for triple-negative breast cancer Meyer, E, Steenbrugge, J, Perera, T, Demeyere, K, Vander Elst, N, Van Den Broeck, W, Sanders, NN, De Wever, O, Ciamporcero, E	NPJ Breast Cancer	2021
20484018	ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity Leggett, DS, Munshi, N, France, DS, Hill, J, Moussa, MM, Li, CJ, Li, Y, Jeay, S, Chen, CR, Ashwell, MA	Mol Cancer Ther	2010
20145145	MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor Kohl, NE, Kunii, K, Davis, LJ, Hatch, H, Zeng, Q, Lu, W, Paweletz, CP, Gibbs, JB, Chan, GK, Kariv, I, Jewell, JP, Gil, S, Szewczak, AA, Reilly, JF, Qu, X, Katz, JD, Chi, A, Deshmukh, SV, Chenard, M, Lutterbach, BA, Dinsmore, CJ, Hang, G, Pan, BS	Cancer Res	2010
29674709	Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy Comoglio, PM, Boccaccio, C, Trusolino, L	Nat Rev Cancer	2018
21655918	Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks Fujiwara, Y, Mukohara, T, Kataoka, Y, Tomioka, H, Minami, H, Hirakawa, K, Yashiro, M, Kiyota, N, Funakoshi, Y, Hirai, M	Invest New Drugs	2012
28131876	Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib Zhang, YK, Yu, XY, Zhu, XJ, Barbuti, AM, Zhang, GN, Chen, ZS, Wen, AW, Wang, YJ, Wurpel, JND	Pharmacol Res	2017
24700742	Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET Wang, J, Shang, C, Chen, W, Xiang, Q, Chen, Y, Ren, M, Deng, DY, Zhang, L, Zhang, H	Clin Cancer Res	2014
25148209	Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer Cui, Y, Wang, J, Fan, S, Wang, Q, Gu, Y, Zhang, Z, Weng, J, Zhou, F, Qing, W, Jia, H, Dai, G, Zhou, J, Jiao, L, Su, W, Sai, Y, Ren, Y	J Med Chem	2014
21926191	Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth Shi, Y, Orf, J, Yamaguchi, K, Engst, S, Chou, YC, Chen, J, Yu, P, Tan, J, Laird, AD, Bentzien, F, Joly, AH, Yakes, FM, Lee, L, You, A, Cancilla, B, Lesch, J, Chu, F, Qian, F	Mol Cancer Ther	2011
19808973	Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases Greshock, J, Tam, D, Zaks, T, Mock, L, Yamaguchi, K, Engst, S, Tan, J, Yu, P, Bentzien, F, Joly, AH, Wooster, R, Lougheed, J, Xu, W, Yakes, FM, Li, C, Qian, F, Lou, T, Won, KA	Cancer Res	2009
25248999	Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models Lv, J, Gavine, PR, Fan, S, Wang, L, Han, L, Su, X, Xu, W, Wang, QM, Wang, H, Liu, YJ, Zhang, W, Zhou, F, Qing, W, Fu, H, Jiao, L, Yin, X, Su, W, Xie, L, Zhang, T, Xu, S, Yu, Y, Ren, Y	Mol Oncol	2015
30934578	Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents Zhou, Y, Yan, M, Li, XS, Zhang, NN, An, BJ	Molecules	2019
14612533	A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo Chen, J, Ruslim, L, Cui, JJ, Cherrington, JM, Blake, R, Kuruganti, P, Ramphal, J, Do, S, Lipson, KE, Wang, X, Burrows, J, Chan, E, Le, P, Schreck, R, Christensen, JG, Mendel, DB	Cancer Res	2003
19832844	E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models Asada, M, Yamaguchi, A, Obaishi, H, Funasaka, S, Matsushima, T, Nakagawa, T, Takahashi, K, Tohyama, O, Shirotori, S	Cancer Sci	2010
17325667	A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors Swart, R, Bearss, D, Simons, B, Cooke, L, Wisner, L, Della Croce, K, Riley, C, Garewal, H, Mahadevan, D, Iorio, M, Nagle, R, Shakalya, K	Oncogene	2007
27196782	In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models Dussault, I, Werner, J, Moriguchi, J, Zhang, Y, Hughes, PE, Choquette, DM, Coxon, A, Radinsky, R, Kaplan-Lefko, PJ, Kendall, R, Caenepeel, S, Burgess, TL, Broome, MA, Damore, MA, Amore, B, Yang, Y, Harmange, JC, Rex, K, Baker, D, Kha, HT	Mol Cancer Ther	2016
21918175	A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3 Hall, LM, Liu, X, Yao, W, Scherle, PA, Newton, RC, Yang, G, Xu, M, Wang, Q, Wynn, R, He, C, Diamond, S, Boer, J, Behshad, E, Li, Y, Koblish, HK, Zhuo, J, Fridman, JS, Marando, C	Clin Cancer Res	2011
24233399	Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells Zhang, R, Yao, HP, Hu, X, Zhou, YQ, Wang, MH, Sharma, S, Zeng, JY	Mol Cancer Ther	2014
24326130	Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines Shentu, S, Phillip, CJ, Zaman, S, Stellrecht, CM, Baladandayuthapani, V, Wang, M, Taverna, P, Gandhi, V, Zhang, J, Redkar, S, Balakrishnan, K	J Hematol Oncol	2013
19934279	SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo Do, TH, Leon, BC, Smyth, L, Holme, K, Peterman, MC, Reich, SH, Thompson, DA, Emtage, S, Aubol, BE, Buchanan, SG, Hendle, J, Schwinn, KD, Russell, M, Sauder, JM, Gessert, SF, Smith, CR, Adams, J, Burley, SK, Pelletier, LA, Jessen, KA, Rooney, IA, Bounaud, PY, Blaney, JM, Huser, NH, Sprengeler, PA, Froning, KJ, Wasserman, SR, Lee, PS, Atwell, S, Tang, CM, Felce, JD	Mol Cancer Ther	2009
	Abstract 4791: OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models Lu, T, Wroblowski, B, Libouban, M, Jovcheva, E, Ogata, S, Mevellec, L, Perera, T, Clack, G, Janssens, B, De Lange, D, Verhulst, T
17483355	An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms Alton, G, Nambu, MD, Arango, ME, Koudriakova, TB, Zou, HY, Los, G, Bender, SL, Li, Q, Cui, JJ, Mroczkowski, B, Lee, JH, McDonnell, SR, Yamazaki, S, Christensen, JG, Kung, PP	Cancer Res	2007
31940916	Tivantinib, A c-Met Inhibitor in Clinical Trials, Is Susceptible to ABCG2-Mediated Drug Resistance Wu, ZX, Wang, JQ, Teng, QX, Lusvarghi, S, Yang, Y, Chen, ZS, Ambudkar, SV, Lei, ZN, Wang, JQ, Yang, DH	Cancers (Basel)	2020
28765324	Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models Shapiro, GI, Chudova, DI, Patel, SP, Lee, M, Tassell, V, Aranda, R, Lanman, RB, Chao, R, Baños, N, Essenburg, CJ, Madaj, Z, Christensen, JG, Hidalgo, M, Lopez-Casas, PP, Peled, N, Jänne, PA, Awad, MM, Menendez, C, Graveel, C, Nishino, M, Olson, P, Hallin, J, Briere, D, Tovar, EA, Engstrom, LD, Chiang, H, Bazhenova, L	Clin Cancer Res	2017