Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3, 4-d]pyrimidin-4-amino scaffold. Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: Yin, Yuan; Chen, Cheng-Juan; Yu, Ru-Nan; Shu, Lei; Zhang, Tian-Tai; Zhang, Da-Yong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 8(2019)
• Page Start: 1562
• Page End: 1576
• Publication Date: 2019-04-15
• Subjects: JAK2 -- Inhibitor -- 1H-pyrazolo[3, 4-d]pyrimidin-4-amino -- Intramolecular hydrogen bond; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.02.054
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A series of 1 H -pyrazolo[3, 4- d ]pyrimidin-4-amino derivatives has been synthesized and identified as potent JAK2 inhibitors. 11g had 36-58 fold selectivity against two other JAK-family proteins JAK1 and JAK3. Compounds (11f, 11g ) displayed higher potency against the leukemia cell line TF-1 than tofacitinib. 11g displayed stronger antiproliferative activity against the spleen cell than tofacitinib. Abstract: Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1 H -pyrazolo[3, 4- d ]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3, 5-disubstituted-1 H -pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors11f, 11g, 11h and11k displayed strong activity and selectivity against the JAK2 kinase, with IC50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound11g also in cells. Furthermore, compound11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.