Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity

Abstract

STAT3 belongs to the signal transducers and activators of transcription (STAT) family. It has been demonstrated that STAT3 is constitutively activated in many tumors, playing a role in carcinogenesis and tumor progression. For this reason, it has being considered a potential target for cancer therapy. In this context, we have designed, synthesized and evaluated 1,4-dimethyl-carbazole derivatives, targeting the STAT3 protein. Moreover, MTT assay performed on A375 and HeLa, showed significant antiproliferative activity of some of synthesized compounds (3-5). The same compounds (3-5) considerably reduced STAT3 expression, as demonstrated by Western blot analysis. Our multidisciplinary approach shows that 1,4-dimethyl-carbazoles are potential building blocks to develop more affinity ligands of STAT3.

Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis

“…Additionally, most inhibitors targeting the SH2 domain are not STAT3-specific, which makes it difficult to rule out the roles of other STATs in atherosclerosis 72. Furthermore, due to the difficulty of developing small molecules capable of disrupting protein-protein interactions over a large surface area that still retain drug-like properties, only a limited number of SH2 domain inhibitors have reached preclinical and clinical trials 225-228.…”

Evaluation of quantitative assays for the identification of direct signal transducer and activator of transcription 3 (STAT3) inhibitors

“…Small molecules designed to target this domain, such as S3I-1757 (Figure 2), aim to disrupt the protein-protein interaction of the SH2 domains of activated STAT3 monomers [12]. Due to the difficulty in developing small molecules capable of disrupting protein-protein interactions over a large surface area, while maintaining drug-like properties, there are a limited number of SH2 domain inhibitors that have reached pre-clinical and clinical trials [10, 15, 17, 18]. Stattic was one of the first small molecule inhibitors of STAT3 to be identified [10, 19], and it was initially believed to be a SH2 domain inhibitor; however, it was later determined that its inhibitory activity was due to modification of the protein through covalent interactions with cysteine residues, many of which reside in the DNA-binding domain (DBD) of STAT3 (Figures 1B and 1C) [20, 21].…”

“…Targeting this domain may prove more successful in abrogating STAT3 activity in cancer, as these compounds have the potential to inhibit STAT3 transcriptional activity regardless of dimerization status [10]. This prospective success may be due in part to the ability of unphosphorylated STAT3 to be transcriptionally active [18, 25, 26], and the observation that inhibition of active STAT3 dimers alone may not be sufficient in modulating STAT3 activity [23]. …”

Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

“…III ‐ 4 firstly tested the inhibition of phosphorylation of downstream signal STAT proteins in human peripheral blood mononuclear cells (PBMCs) . The different cellular stimuli used induce phosphorylation of STATs (pSTAT) by either dual JAK1/3 (IL‐2 stimulus, STAT5 phosphorylation), JAK2 (GM‐CSF stimulus, STAT5 phosphorylation), or multiple JAK1/JAK2/TYK2 (IL‐6 stimulus, STAT3 phosphorylation) containing pathways . As exhibited in Table , III ‐ 4 showed a 14.7‐fold selectivity for inhibition of the IL‐2 readout (IC 50 = 40.19 nM) versus the IL‐6 readout (IC 50 = 591.6 nM), and a 12.2‐fold selectivity for inhibition of the GM‐CSF readout (IC 50 = 492 nM).…”