2. Academic Validation
  3. Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM)

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM)

  • Eur J Med Chem. 2015 Oct 20:103:210-22. doi: 10.1016/j.ejmech.2015.08.001.
Ahmed Elkamhawy 1,  Ambily Nath Indu Viswanath 2,  Ae Nim Pae 2,  Hyeon Young Kim 3,  Jin-Chul Heo 3,  Woo-Kyu Park 3,  Chong-Ock Lee 3,  Heekyoung Yang 4,  Kang Ho Kim 4,  Do-Hyun Nam 5,  Ho Jun Seol 5,  Heeyeong Cho 6,  Eun Joo Roh 7
Affiliations

Affiliations

  • 1 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 2 Center of Neuromedicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Medicinal and Pharmaceutical Chemistry, Korea University of Science and Technology (UST), Daejeon 305-343, South Korea.
  • 3 Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea.
  • 4 Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea.
  • 5 Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, South Korea.
  • 6 Department of Medicinal and Pharmaceutical Chemistry, Korea University of Science and Technology (UST), Daejeon 305-343, South Korea; Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea. Electronic address: hycho@krict.re.kr.
  • 7 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea. Electronic address: r8636@kist.re.kr.
PMID: 26355532 DOI: 10.1016/j.ejmech.2015.08.001
Abstract

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 [(3)H] 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.

Keywords

Clonogenic assay; Docking; Glioblastoma multiforme (GBM); Mitochondrial permeability transition pore (mPTP); Quinazoline-urea; Toxicity profile; Translocator protein 18 kDa (TSPO).

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