title: Identification of two novel RET kinase inhibitors through MCR-based drug discovery: design, synthesis and evaluation.
abstract: From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Frett
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Naples, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Moccia
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 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", 80131 Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA; The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. Electronic address: hongyuli@pharmacy.arizona.edu.
authors.forename: Hong-yu
authors.initials: HY
authors.lastname: Li
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret
keywords: Kinase; Lead discovery; MCR; Medicinal chemistry; RET; Targeted therapeutics