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제116회 대한화학회 학술발표회, 총회 및 기기전시회 안내 The Discovery of 2,5-Isomers of Triazole-pyrrolopyrimidine as Novel Selective and Potent Janus Kinase 2 Inhibitors [우수포스터상]

2015년 8월 27일 16시 54분 57초
MEDI.P-507 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 15일 (목요일) 11:00~12:30
저자 및
이선미, 고효진1,*
광주과학기술원(GIST) 의료시스템학과, Korea
1광주과학기술원(GIST) 생명과학부, Korea
Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutated JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs) and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective JAK2 inhibitor based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. (1) Among all triazole compounds, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activities than other isomers with substitutions of various alkyl groups at the R2 position, except for methyl substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. (2) None of the synthesized 1,4-isomers inhibited the three JAK family members. (3) Compounds with phenyl or tolyl group substituents at the R1 position were completely inactive compared with the corresponding methyl substituted analogues at the R1 position. As a result of this structure-activity relationship, 54 substituted with a cyclopropylmethyl moiety exhibited significant inhibitory activity and selectivity. (IC50 = 41.9 nM, selectivity fold JAK1/2 10.6 and JAK3/2 58.1). Compound 54 exhibited equivalent inhibitory potency of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which feature JAK2 V617F, and gefitinib-resistant HCC827 cells; compound 54 also suppressed STAT3 phosphorylation of Y705.