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 from in vitro protein kinase inhibition experiments indicated that compounds 3a−f and 11b are potent JAKs inhibitors. For example, the IC 50 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 (IC 50 : 0.35 μM) and K562 (IC 50 : 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: JAKs, Inhibitors, 4-Amino-(1H)-pyrazole, Anticancer T he JAK/STAT signaling pathway plays critical roles in immunity, hematopoiesis, and cell growth.1 Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancers.2 Constitutive activations of JAKs are correlated to oncogenesis. Dysregulation of JAK2 is discovered in patients with myeloproliferative neoplasms and childhood T cell acute lymphoblastic leukemia. 3Several hematologic malignancies including malignant lymphoma and myeloproliferative disorders are associated with mutations of JAK2.4 Some cytokines and growth factors bind to their receptors and then stimulate JAKs for the phosporylation of STAT3, which is a potential target for anticancer therapy. 6 Thus, the JAK/STAT signaling pathway is a promising antitumor target.Inhibitors of JAKs are widely explored for treatment of immunodeficiency, inflammation, and cancer. Among the synthetic JAK inhibitors for the treatment of cancer identified to date (Figure 1), Ruxolitinib (Incyte's Jakafi) was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of myelofibrosis, a rare bone marrow cancer. Besides, it is in phase III clinical trials for the treatment of metastatic pancreatic cancer and phase II clinical trials for the treatment of multiple myeloma, leukemia, and colon cancer. 7 There are several other JAKs inhibitors in clinical trials for cancer treatment (Figure 1). JAK2 inhibitor AZD1480 can inhibit STAT5 signaling in prostate cancer cells and then effectively inhibit castration-resistant growth of prostate cancer.8 JAK2 inhibitor TG101348 blocks JAK/STAT signaling leading to suppression of proliferation and induction of apoptosis and is used for the treatment of myelofibrosis.9 JAKs inhibitors Momelotinib and

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

“…The three series were composed of three different central rings—a pyrimdine ring, a quinazoline fused ring and a pyrrolo[2,3- d ]pyrimidine fused ring. Additional variations to the structures to investigate SAR were sought, such as changing the tether link’s length between the phenylamine derivative and the central heterocycle ring and having a different substituent on the distal phenyl ring ( Figure 44 ) [ 55 ].…”

Micelle-Mediated Chemistry in Water for the Synthesis of Drug Candidates

“…114 Aniline 50 has in turn been elaborated using non-micellar or micellar methods to aminopyrimidine 51, 115 a compound that features in the synthesis of kinase inhibitors co-targeting IGF1R and EG-FR L858R/T790M , 117 as well as AXL 118 and the JAK-STAT signalling pathway. 119 Other examples of the application of a nitro reduction in a micellar medium include the synthesis of procainamide (52), and aminothiazole 53 used to make fructose 1,6-bisphosphatase inhibitors 120 and antimicrobial drug candidates (Scheme 15). 121…”

Synthesis of Antimicrobial Benzimidazole–Pyrazole Compounds and Their Biological Activities

“…Additionally, benzimidazoles treat mitochondrial dysfunction in Alzheimer’s disease [ 22 ], possess neurotropic, psychoactive, analgesic effects [ 23 ], anticoagulant proprieties [ 24 ] and are efficient agents in Diabetes mellitus [ 25 ]. Additionally, pyrazole compounds possess a diversity of biological activities as analgesic [ 26 , 27 , 28 ], anticonvulsivant [ 29 , 30 ], antitumor [ 31 , 32 , 33 , 34 ], antidiabetic [ 35 , 36 ], antimicrobial [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ], antipyretic [ 44 , 45 ], antiviral [ 46 , 47 ], antimalarial [ 48 , 49 ], local anesthetic [ 50 ] and so forth.…”