Identification of a novel 5-amino-3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-1H-pyrazole-4-carboxamide as a specific RET kinase inhibitor.
Activating mutations of REarrange during Transfection (RET) kinase frequently occur in human thyroid and lung cancers. An enormous effort has been devoted to discover potent and selective inhibitors of RET. Selective and potent inhibitors against constitutively active RET mutants are rare to date as identification of selective RET inhibitors is challenging. In a recent effort we identified a novel and specific RET inhibitor of 5-aminopyrazole-4-carboxamide scaffold, which was designed to enhance the metabolic stability of the pyrazolopyrimidine scaffold. In the SAR study described in the current report, we identified the 5-aminopyrazole-4-carboxamide analog 15l, which displays high metabolic stability. Compound 15l is potent against gatekeeper mutant (IC50= 252 nM) of RET as well as against wild-type RET (IC50= 44 nM). This substance effectively suppresses growth of Ba/F3 cells transformed with wild-type RET and its gatekeeper mutant (V804M), and thyroid-cancer derived TT cells while it does not affect parental Ba/F3 cells and Nthy ori-3-1, normal thyroid cells. Also, the results of a global kinase profiling assay on a panel of 369 kinases, show that 15l exclusively inhibits RET. Based on its exceptional kinase selectivity, great potency and metabolic stability, 15l represents a promising lead for the discovery of RET directed therapeutic agent and should be a key tool in studies aimed at understanding RET biology.
Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Hojong
H
Yoon
KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
Injae
I
Shin
KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
Yunju
Y
Nam
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
Nam Doo
ND
Kim
Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Daejeon 34133, Republic of Korea.
Kyung-Bok
KB
Lee
Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address: tbsim@kist.re.kr.
Taebo
T
Sim
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*
C000604556:5-aminopyrazole; D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D051096:Proto-Oncogene Proteins c-ret
5-Aminopyrazole-4-carboxamide; Metabolic stability; RET kinase; Specific inhibitor