title: Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors.
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 fromin vitroprotein kinase inhibition experiments indicated that compounds3a-fand11bare potent JAKs inhibitors. For example, the IC50values of compound3fagainst JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound3fshowed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound11bshowed selective cytotoxicity at submicromolar levels against HEL (IC50: 0.35 μM) and K562 (IC50: 0.37 μM) cell lines. It is worth noting that both3fand11bshowed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.
authors: Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
authors: Xuewu
authors: X
authors: Liang
authors: Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
authors: Jie
authors: J
authors: Zang
authors: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30303, United States.
authors: Mengyuan
authors: M
authors: Zhu
authors: Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
authors: Qianwen
authors: Q
authors: Gao
authors: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30303, United States.
authors: Binghe
authors: B
authors: Wang
authors: Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
authors: Wenfang
authors: W
authors: Xu
authors: Department of Medicinal Chemistry, School of Pharmacy, Shandong University , Ji'nan, Shandong 250012, P. R. China.
authors: Yingjie
authors: Y
authors: Zhang
keywords: 4-Amino-(1H)-pyrazole; Anticancer; Inhibitors; JAKs