{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:43:51Z","timestamp":1788983031948,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2018R1A2B6001299 and NRF-2020R1A2C2005690"],"award-info":[{"award-number":["NRF-2018R1A2B6001299 and NRF-2020R1A2C2005690"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Two novel bioisosteres of cabozantinib, 3 and 4, were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (3) and pyridine (4), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal\u2013epithelial transition factor (c-Met) inhibitory activities at 1 \u03bcM concentration (4% inhibition of 3 vs. 94% inhibition of 4). The IC50 value of compound 4 was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that 4 includes the preferred conformation for the binding to c-Met in the conformational ensemble, but 3 does not. The anti-proliferative activity of compound 4 against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas 3 did not show a significant anti-proliferative activity. Moreover, the tumor selectivity of compound 4 toward hepatocellular carcinoma cell lines was higher than that of cabozantinib. In the xenograft chick tumor model, compound 4 inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound 4 may be a good therapeutic candidate against hepatocellular carcinoma.<\/jats:p>","DOI":"10.3390\/ijms22189685","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T10:24:25Z","timestamp":1631010265000},"page":"9685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Novel Pyridine Bioisostere of Cabozantinib as a Potent c-Met Kinase Inhibitor: Synthesis and Anti-Tumor Activity against Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8483-7120","authenticated-orcid":false,"given":"Ujjwala","family":"Karmacharya","sequence":"first","affiliation":[{"name":"College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diwakar","family":"Guragain","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Goo","family":"Jee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0824-8532","authenticated-orcid":false,"given":"Jung-Ae","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7814-6638","authenticated-orcid":false,"given":"Byeong-Seon","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1126\/science.1846706","article-title":"Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product","volume":"251","author":"Bottaro","year":"1991","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2174\/0929867323666161028161441","article-title":"Recent Advances in the Design and Synthesis of c-Met Inhibitors as Anticancer Agents (2014\u2013Present)","volume":"24","author":"Lv","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5766","DOI":"10.1021\/jm8006189","article-title":"Design, synthesis, and biological evaluation of potent c-Met inhibitors","volume":"51","author":"Bellon","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"588","DOI":"10.2183\/pjab.86.588","article-title":"The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine","volume":"86","author":"Nakamura","year":"2010","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_5","first-page":"148","article-title":"Targeting MET in cancer therapy","volume":"3","author":"Mo","year":"2017","journal-title":"Chronic Dis. Transl. Med."},{"key":"ref_6","first-page":"811","article-title":"Expression of hepatocyte growth factor and its receptor c-met, correlates with severity of pathological injury in experimental alcoholic liver disease","volume":"15","author":"Lalani","year":"2005","journal-title":"Int. J. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.jhep.2013.09.009","article-title":"Met as a therapeutic target in HCC: Facts and hopes","volume":"60","author":"Giordano","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1080\/17460441.2019.1551355","article-title":"Optimization techniques for novel c-Met kinase inhibitors","volume":"14","author":"Sun","year":"2019","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.2147\/OTT.S231257","article-title":"MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF\/c-Met Axis","volume":"13","author":"Liang","year":"2020","journal-title":"Onco Targets Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.jtho.2016.04.033","article-title":"Identifying the Appropriate FISH Criteria for Defining MET Copy Number-Driven Lung Adenocarcinoma through Oncogene Overlap Analysis","volume":"11","author":"Noonan","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1158\/0008-5472.CAN-04-2650","article-title":"Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer","volume":"65","author":"Ma","year":"2005","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fcell.2020.00055","article-title":"The Function of the HGF\/c-Met Axis in Hepatocellular Carcinoma","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.pharmthera.2013.12.014","article-title":"The Met receptor tyrosine kinase: A key player in oncogenesis and drug resistance","volume":"142","author":"Maroun","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3695","DOI":"10.3748\/wjg.v24.i33.3695","article-title":"Updates on the hepatocyte growth factor\/c-Met axis in hepatocellular carcinoma and its therapeutic implications","volume":"24","author":"Medina","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1038\/sj.bjc.6601718","article-title":"The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients","volume":"90","author":"Masuya","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dimou, A., Non, L., Chae, Y.K., Tester, W.J., and Syrigos, K.N. (2014). MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107677"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1177\/1758834011422556","article-title":"An overview of the c-MET signaling pathway","volume":"3","author":"Organ","year":"2011","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4876","DOI":"10.1158\/1078-0432.CCR-06-0362","article-title":"Presence of phosphorylated hepatocyte growth factor receptor\/c-Met is associated with tumor progression and survival in patients with conventional renal cell carcinoma","volume":"12","author":"Miyata","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/13543784.2018.1462336","article-title":"C-MET inhibitors for advanced non-small cell lung cancer","volume":"27","author":"Pasquini","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5445","DOI":"10.3748\/wjg.v21.i18.5445","article-title":"MET inhibitors for treatment of advanced hepatocellular carcinoma: A review","volume":"21","author":"Qi","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.1021\/jm2007613","article-title":"Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)","volume":"54","author":"Cui","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1200\/JCO.2012.48.4659","article-title":"Cabozantinib in progressive medullary thyroid cancer","volume":"31","author":"Elisei","year":"2013","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1080\/14737140.2017.1344553","article-title":"Cabozantinib for the treatment of kidney cancer","volume":"17","author":"Abdelaziz","year":"2017","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2174\/1871520611009010007","article-title":"Discovery of small molecule c-Met inhibitors: Evolution and profiles of clinical candidates","volume":"10","author":"Underiner","year":"2010","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1021\/jm401427c","article-title":"Targeting receptor tyrosine kinase MET in cancer: Small molecule inhibitors and clinical progress","volume":"57","author":"Cui","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_26","first-page":"281","article-title":"In silico identification of bioisosteric functional groups","volume":"10","author":"Ertl","year":"2007","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/minf.201000019","article-title":"Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization","volume":"29","author":"Langdon","year":"2010","journal-title":"Mol. Inform."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Dick, A., and Cocklin, S. (2020). Bioisosteric Replacement as a Tool in Anti-HIV Drug Design. Pharmaceuticals, 13.","DOI":"10.3390\/ph13030036"},{"key":"ref_29","first-page":"1","article-title":"The use of bioisosterism in drug design and molecular modification","volume":"2","author":"Gaikwad","year":"2012","journal-title":"Am. J. PharmTech Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1039\/C6OB00406G","article-title":"5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: Design, synthesis and cytotoxicity against cancer cells","volume":"14","author":"Shah","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ejmech.2014.03.045","article-title":"6-Amino-2,4,5-trimethylpyridin-3-ols: A new general synthetic route and antiangiogenic activity","volume":"78","author":"Kim","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chaudhary, C.L., Chaudhary, P., Dahal, S., Bae, D., Nam, T.G., Kim, J.A., and Jeong, B.S. (2020). Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol. Bioorg. Med. Chem., 103.","DOI":"10.1016\/j.bioorg.2020.104130"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1021\/acs.jcim.9b00373","article-title":"Comprehensive Assessment of Torsional Strain in Crystal Structures of Small Molecules and Protein-Ligand Complexes using ab Initio Calculations","volume":"59","author":"Rai","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/ci100031x","article-title":"Conformer generation with OMEGA: Algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database","volume":"50","author":"Hawkins","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1021\/jm0603365","article-title":"Comparison of shape-matching and docking as virtual screening tools","volume":"50","author":"Hawkins","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41417-019-0098-6","article-title":"Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT\/GSK-3\u03b2\/NF-\u03baB signaling pathway","volume":"27","author":"Yang","year":"2020","journal-title":"Cancer Gene. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e525","DOI":"10.1016\/j.ijrobp.2012.06.025","article-title":"Higher levels of c-Met expression and phosphorylation identify cell lines with increased sensitivity to AMG-458, a novel selective c-Met inhibitor with radiosensitizing effects","volume":"84","author":"Li","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1080\/15384101.2016.1152428","article-title":"Hepatic stellate cell promoted hepatoma cell invasion via the HGF\/c-Met signaling pathway regulated by p53","volume":"15","author":"Liu","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0092-8674(94)90318-2","article-title":"A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor\/scatter factor receptor family","volume":"77","author":"Ponzetto","year":"1994","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/1477-3163.44372","article-title":"Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer","volume":"7","author":"Puri","year":"2008","journal-title":"J. Carcinog."},{"key":"ref_41","first-page":"48","article-title":"Epidermal growth factor receptor (EGFR) in lung cancer: An overview and update","volume":"2","author":"Bethune","year":"2010","journal-title":"J. Thorac. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41419-020-2558-1","article-title":"Differential effectiveness of tyrosine kinase inhibitors in 2D\/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells","volume":"11","author":"Cadenas","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"29565","DOI":"10.1074\/jbc.M403954200","article-title":"A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl\/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation","volume":"279","author":"Peschard","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/onc.2009.88","article-title":"Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity","volume":"28","author":"Ancot","year":"2009","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/carcin\/bgw015","article-title":"Regulation of the MET oncogene: Molecular mechanisms","volume":"37","author":"Zhang","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/cas.12891","article-title":"Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells","volume":"107","author":"Koc","year":"2016","journal-title":"Cancer Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9685\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:58:14Z","timestamp":1760165894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9685"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,7]]},"references-count":46,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189685"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189685","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,7]]}}}