title: Preparation of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines as RET kinase inhibitors.
abstract: A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Dinér
authors.forename: John P
authors.initials: JP
authors.lastname: Alao
authors.forename: Johan
authors.initials: J
authors.lastname: Söderlund
authors.forename: Per
authors.initials: P
authors.lastname: Sunnerhagen
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D051096:Proto-Oncogene Proteins c-ret; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3