Design,Synthesis And SAR Analysis Of Novel STAT3 Inhibitors With Anti-cancer Activities

The treatment of cancer undergo three periods were chemotherapy,targeted therapy,and immunotherapy.Both chemotherapy and target therapy are directly targeted to the cancer cell itself,which can significantly prolong the progression free survival(PFS)of the tumor patients,immunotherapy is mainly used to kill cancer cells indirectly by acting on tumor related immune cells,which not only prolongs PFS but also improves the Overall survival(OS)of tumor patients.The successful approved monoclonal antibodies of CTLA-4 and PD-1/PD-L1,indicated that immunotherapy has emerged as a one of major therapeutic modality in oncology.Signal transducer and activator of transcription 3(STAT3)is a transcription factor that regulates the expression of genes mediated regulating cell growth,proliferation,differentiation and apoptosis in normal cells by cytokines and growth factors.Recently studies showed that inhibition of STAT3 not only directly acts on tumor cells to inhibit tumor growth and metastasis,but also regulates tumor related immune cells to play the role of tumor immunotherapy.AZD9150,an antisense oligonucleotide inhibitor of STAT3 was proved with early evidence of clinical activity in lymphoma and lung cancer.Seven clinical studies assessing the preliminary anti-tumor activity of AZD9150 in combination with PD-L1 monoclonal antibody had been entered phase 2.Another STAT3 single domain antibody SBT-100 was also obtained the granted of FDA orphan drug status in pancreatic cancer and sarcoma in 2016 and 2017.However the specific small molecule STAT3 inhibitors,C188-9 and BP-1-102,were currently in human trials,morever they were only micromolar levels tageting STAT3.Compared with macromolecule STAT3 inhibitor there is still much more potent activity for improvement,so our research was focus on the design and synthesis of potent,specific small molecular STAT3 inhibitors.Using Structure-Based Drug Design(SBDD)and Docking technology we designed and synthesized 2-amino-3-cyano thiophene derivatives against cancer by targeting STAT3.To develop novel,selective and potent STAT3 inhibitors,the benzo[b]thiophene 1,1-dioxide,as in Stattic,was employed as a leading scaffold.Three classes of 2-amino-3-cyanthiophene derivatives were synthesized by chemical modification,which are alkylation,acylation and urea alkylation.The structure-activity relationship shows that its inhibitory activity to STAT3 is urea substitution >acylation substitution >alkylation.The most selective and potent STAT3 inhibitor BP-1-102(KD = 1.79 ?M)was reported from the published articles,our studies found three compounds as ten times more than BP-1-102,respectively 5o(KD = 0.19 ?M),5n(KD = 0.13 ?M)and 8g(KD = 0.24 ?M).STAT3 inhibitors 5p and 7r not only have potent anti-tumor effects in vitro,but also have the same anti-tumor growth and metastasis effects in pancreatic cancer and osteosarcoma in vivo.The STAT3 inhibitors 2-amino-3-cyano thiophene derivatives were a promising clinical candidate for further development.