| Structural highlights
Disease
MET_HUMAN Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:114550.[1] Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:605074. It is a subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into common renal cell carcinoma (clear cell, non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.[2] [3] [4] [5] [6] Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.[7]
Function
MET_HUMAN Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.[8] [9] [10] Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.[11] [12] [13]
Publication Abstract from PubMed
Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC(50) value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.
Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.,Bumpers QA, Pipal RW, Benz-Weeden AM, Brewster JT 2nd, Cook A, Crooks AL, Cruz C, Dwulet NC, Gaudino JJ, Golec D, Harrison JA, Hartley DP, Hassanien SH, Hicken EJ, Kahn D, Laird ER, Lemieux C, Lewandowski N, McCown J, McDonald MG, McNulty O, Mou TC, Nguyen P, Oko L, Opie LP, Otten J, Peck SC, Polites VC, Randall SD, Rosen RZ, Savechenkov P, Simpson H, Singh A, Sparks D, Wickersham K, Wollenberg L, Wong CE, Wong J, Wu WI, Elsayed MSA, Hinklin RJ, Tang TP J Med Chem. 2024 Aug 1. doi: 10.1021/acs.jmedchem.4c01232. PMID:39088797[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schmidt L, Zbar B, Lee JY. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999 Jan 15;59(2):307-10. PMID:9927037
- ↑ Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997 May;16(1):68-73. PMID:9140397 doi:10.1038/ng0597-68
- ↑ Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 1998 Apr 15;58(8):1719-22. PMID:9563489
- ↑ Lubensky IA, Schmidt L, Zhuang Z, Weirich G, Pack S, Zambrano N, Walther MM, Choyke P, Linehan WM, Zbar B. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999 Aug;155(2):517-26. PMID:10433944 doi:10.1016/S0002-9440(10)65147-4
- ↑ Olivero M, Valente G, Bardelli A, Longati P, Ferrero N, Cracco C, Terrone C, Rocca-Rossetti S, Comoglio PM, Di Renzo MF. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int J Cancer. 1999 Aug 27;82(5):640-3. PMID:10417759
- ↑ Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999 Apr 8;18(14):2343-50. PMID:10327054 doi:10.1038/sj.onc.1202547
- ↑ Stella GM, Benvenuti S, Gramaglia D, Scarpa A, Tomezzoli A, Cassoni P, Senetta R, Venesio T, Pozzi E, Bardelli A, Comoglio PM. MET mutations in cancers of unknown primary origin (CUPs). Hum Mutat. 2011 Jan;32(1):44-50. doi: 10.1002/humu.21374. Epub 2010 Nov 9. PMID:20949619 doi:10.1002/humu.21374
- ↑ Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802-4. PMID:1846706
- ↑ Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Archer C, Rosen EM, Madara JL. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J Clin Invest. 1994 May;93(5):2056-65. PMID:8182137 doi:http://dx.doi.org/10.1172/JCI117200
- ↑ Higuchi T, Orita T, Katsuya K, Yamasaki Y, Akiyama K, Li H, Yamamoto T, Saito Y, Nakamura M. MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met. Mol Cell Biol. 2004 Sep;24(17):7456-68. PMID:15314156 doi:10.1128/MCB.24.17.7456-7468.2004
- ↑ Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802-4. PMID:1846706
- ↑ Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Archer C, Rosen EM, Madara JL. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J Clin Invest. 1994 May;93(5):2056-65. PMID:8182137 doi:http://dx.doi.org/10.1172/JCI117200
- ↑ Higuchi T, Orita T, Katsuya K, Yamasaki Y, Akiyama K, Li H, Yamamoto T, Saito Y, Nakamura M. MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met. Mol Cell Biol. 2004 Sep;24(17):7456-68. PMID:15314156 doi:10.1128/MCB.24.17.7456-7468.2004
- ↑ Bumpers QA, Pipal RW, Benz-Weeden AM, Brewster JT 2nd, Cook A, Crooks AL, Cruz C, Dwulet NC, Gaudino JJ, Golec D, Harrison JA, Hartley DP, Hassanien SH, Hicken EJ, Kahn D, Laird ER, Lemieux C, Lewandowski N, McCown J, McDonald MG, McNulty O, Mou TC, Nguyen P, Oko L, Opie LP, Otten J, Peck SC, Polites VC, Randall SD, Rosen RZ, Savechenkov P, Simpson H, Singh A, Sparks D, Wickersham K, Wollenberg L, Wong CE, Wong J, Wu WI, Elsayed MSA, Hinklin RJ, Tang TP. Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy. J Med Chem. 2024 Aug 1. PMID:39088797 doi:10.1021/acs.jmedchem.4c01232
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