title: A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
abstract: Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Hojong
authors.initials: H
authors.lastname: Yoon
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.
authors.forename: Yeonui
authors.initials: Y
authors.lastname: Kwak
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.
authors.forename: Seunghye
authors.initials: S
authors.lastname: Choi
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.affiliation: Daegu-Gyeongbuk Medical Innovation Foundation , 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Republic of Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Korea University , 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D010766:Phosphorylation; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C452423:vandetanib