Discovery of Ureido-Substituted 4-Phenylthiazole Derivatives as IGF1R Inhibitors with Potent Antiproliferative Properties.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Receptor, IGF Type 1*/antagonists & inhibitors ; Receptor, IGF Type 1*/metabolism ; Cell Proliferation*/drug effects ; Thiazoles*/chemistry ; Thiazoles*/pharmacology ; Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/chemistry ; Protein Kinase Inhibitors*/chemical synthesis ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Apoptosis*/drug effects; Humans ; Hep G2 Cells ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Liver Neoplasms/metabolism ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/metabolism ; Cell Movement/drug effects ; Structure-Activity Relationship ; Molecular Docking Simulation ; Receptors, Somatomedin/antagonists & inhibitors ; Receptors, Somatomedin/metabolism ; Molecular Structure ; Cell Line, Tumor ; Sorafenib/pharmacology ; Sorafenib/chemistry ; Models, Molecular

The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC 50 = 0.62 ± 0.34 μM), significantly exceeding Sorafenib (IC 50 = 1.62 ± 0.27 μM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 μM). Molecular modeling substantiated compound 27 's strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27 . These findings provide a promising drug candidate for the treatment of HCC patients.

J Med Chem. 2015 Jan 8;58(1):466-79. (PMID: 25478866)
Lancet Oncol. 2009 Jan;10(1):25-34. (PMID: 19095497)
Nat Chem Biol. 2006 Jul;2(7):358-64. (PMID: 16783341)
Curr Pharm Des. 2009;15(2):120-33. (PMID: 19149608)
Cancer Treat Rev. 2020 Mar;84:101966. (PMID: 32044644)
Anticancer Agents Med Chem. 2013 Jun;13(5):731-47. (PMID: 23094911)
Int J Clin Oncol. 2020 Sep;25(9):1672-1677. (PMID: 32417993)
J Mol Graph Model. 2020 May;96:107538. (PMID: 31981898)
Surg Oncol. 2021 Dec;39:101663. (PMID: 34583091)
Signal Transduct Target Ther. 2020 Jun 10;5(1):87. (PMID: 32532960)
Drugs. 2001;61(12):1765-74; discussion 1775-6. (PMID: 11693465)
N Engl J Med. 2008 Jul 24;359(4):378-90. (PMID: 18650514)
J Int Med Res. 2023 Jun;51(6):3000605231179928. (PMID: 37314298)
N Engl J Med. 2019 May 16;380(20):1929-1940. (PMID: 31091374)
Bioorg Med Chem Lett. 2011 Apr 1;21(7):2106-12. (PMID: 21353546)
Nat Rev Gastroenterol Hepatol. 2023 Apr;20(4):203-222. (PMID: 36369487)
Comput Biol Chem. 2021 Feb;90:107414. (PMID: 33191109)
Pharmaceuticals (Basel). 2022 Feb 14;15(2):. (PMID: 35215339)
J Med Chem. 2016 May 26;59(10):4859-66. (PMID: 27078757)
Sci Rep. 2016 Apr 15;6:24460. (PMID: 27080011)

202310160003X the Chinese College Student Innovation and Entrepreneurship Training Program; JYTZD201912 the Basic Scientific Research Project (Key Project) of Liaoning Provincial Department of Education; 2023-MSLH-043 he Liaoning Province Science and Technology Plan Joint Program Project; jytms20231744 the Liaoning Provincial Department of Education General Research Project in the field of Natural Science

Keywords: HCC; anticancer; inhibitors; molecular modeling; ureido of 4-phenylthiazole derivatives

EC 2.7.10.1 (Receptor, IGF Type 1)
0 (IGF1R protein, human)
0 (Thiazoles)
0 (Protein Kinase Inhibitors)
0 (Antineoplastic Agents)
0 (Receptors, Somatomedin)
9ZOQ3TZI87 (Sorafenib)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240708

20240708

PMC11173463

10.3390/molecules29112653

38893528