Elkamhawy, Ahmed Viswanath, Ambily Nath Indu Pae, Ae Nim Kim, Hyeon Young Heo, Jin-Chul Park, Woo-Kyu Lee, Chong-Ock Yang, Heekyoung Kim, Kang Ho Nam, Do-Hyun Seol, Ho Jun Cho, Heeyeong Roh, Eun Joo 2024-01-20T06:01:10Z 2024-01-20T06:01:10Z 2021-09-04 2015-10-20 0223-5234 https://pubs.kist.re.kr/handle/201004/124877 Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC50 values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [H-3] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20,22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. (C) 2015 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER TRANSLOCATOR PROTEIN ACCURATE DOCKING CELLS TEMOZOLOMIDE EXPRESSION CHANNEL GLIDE Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM) Article 10.1016/j.ejmech.2015.08.001 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.103, pp.210 - 222 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 103 210 222 scie scopus 000363344700016 2-s2.0-84941135722 Chemistry, Medicinal Pharmacology & Pharmacy Article TRANSLOCATOR PROTEIN ACCURATE DOCKING CELLS TEMOZOLOMIDE EXPRESSION CHANNEL GLIDE Quinazoline-urea Glioblastoma multiforme (GBM) Translocator protein 18 kDa (TSPO) Mitochondrial permeability transition pore (mPTP) Docking Clonogenic assay Toxicity profile