Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
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.
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.
Ahmed
A
Elkamhawy
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.
Ambily Nath Indu
AN
Viswanath
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.
Ae Nim
AN
Pae
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea.
Hyeon Young
HY
Kim
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea.
Jin-Chul
JC
Heo
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea.
Woo-Kyu
WK
Park
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-343, South Korea.
Chong-Ock
CO
Lee
Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea.
Heekyoung
H
Yang
Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea.
Kang Ho
KH
Kim
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.
Do-Hyun
DH
Nam
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.
Ho Jun
HJ
Seol
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.
Heeyeong
H
Cho
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.
Eun Joo
EJ
Roh
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011799:Quinazolines; D003606:Dacarbazine; D014508:Urea; D000077204:Temozolomide
Clonogenic assay; Docking; Glioblastoma multiforme (GBM); Mitochondrial permeability transition pore (mPTP); Quinazoline-urea; Toxicity profile; Translocator protein 18 kDa (TSPO)