Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1 H)-pyrazole Derivatives as JAKs Inhibitors

Xuewu Liang; Jie Zang; Mengyuan Zhu; Qianwen Gao; Binghe Wang; Wenfang Xu; Yingjie Zhang

doi:10.1021/acsmedchemlett.6b00247

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1 H)-pyrazole Derivatives as JAKs Inhibitors

ACS Med Chem Lett. 2016 Aug 23;7(10):950-955. doi: 10.1021/acsmedchemlett.6b00247. eCollection 2016 Oct 13.

Authors

Xuewu Liang¹, Jie Zang¹, Mengyuan Zhu², Qianwen Gao¹, Binghe Wang², Wenfang Xu¹, Yingjie Zhang¹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
² Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30303, United States.

Abstract

Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a-f and 11b are potent JAKs inhibitors. For example, the IC₅₀ values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC₅₀: 0.35 μM) and K562 (IC₅₀: 0.37 μM) cell lines. It is worth noting that both 3f and 11b showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.

Keywords: 4-Amino-(1H)-pyrazole; Anticancer; Inhibitors; JAKs.