title: Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.
abstract: Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Moccia
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Guida
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Federico
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Brescia
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institut Albert Bonniot, CRI INSERM/UJF U823, La Tronche Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Billaud
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts United States of America; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D041681:NIH 3T3 Cells; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017434:Protein Structure, Tertiary; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D014162:Transfection
chemical_list: C000605793:ALW-II-41-27; D001549:Benzamides; C000605795:HG-6-63-01; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; C000605794:XMD15-44; D009536:Niacinamide; D051096:Proto-Oncogene Proteins c-ret