Abstract
Abstract Background, Small molecule inhibitors targeting bromodomain and extraterminal domain (BET) protein is promising for cancer therapy. Previous study show that BRD4 was unregulated in different kind of cancer, with leukemia included, and BETi (BET inhibitors), such as JQ1(+) show evidence to inhibit the proliferation of cancer in vitro and vivo. However, there is no powerful data to evaluate the expression of BRD4, phosphorylation of BRD4 (p-BRD4) and the effectiveness of BETi in small cell lung cancer (SCLC). According to our previous study, BRD4 was highly expressed in 34 SCLC patients (70%) and correlated with poor prognosis in. Method, More than 120 tissue samples and survival data of SCLC patients in Hunan Cancer Hospital were collected. Immunohistochemistry was conducted to evaluate the expression of BRD4, p-BRD4 and the prognosis of these SCLC patients. Based on our previous finding, we design and modify series small molecular compound with carbocycles shape named NHWDs. We use the MTT in SCLC cell lines to evaluate the activity and selected the best. And then potential pathway was demonstrated with Array and Western blot. Finally, the activity of small compounds free base and HCL formation were conducted by xenograft and Patient Derived Xenograft (PDX) with or without double Platinum chemotherapy patients of etoposide and cisplatin resistant. Result, In 120 SCLC formalin-fixed specimens, BRD4 and p-BRD4 was highly expressed in SCLC and correlated with the poor prognosis of SCLC patients. All the compounds, free base and HCL formation which design and modify by ourselves were potent and selective BET family bromodomain inhibitor, not only binds bromodomains of BRD2/3/4/T, but the p-BRD4. Compare with JQ1(+) and other molecular compounds, NHWD-870 free base and NHWD-870-HCL have the best effectiveness and powerful anti-cancer in SCLC, and the IC50 was 1.579nM. NHWD-870 exhibited robust single agent activity in cell viability assay across cell lines in vitro and xenografts of SCLC in vivo by downregulating MYC. Consistent with its broad spectrum of activities in invo, NHWD-870 and NHWD-870-HCL have potent tumor suppressive efficacies in PDX model of SCLC. Monotherapy and combining with antiangiogenesis, such as bevacizumab and apatinib, NHWD-870 and NHWD-870-HCL proved to be more effective in SCLC cell lines and PDX in patients who show resistant to double Platinum chemotherapy with etoposide and cisplatin. Conclusion, NHWD-870 shows to be a powerful anti-cancer drug in SCLC. Further basic and clinical research should be conducted from bench to beside. Citation Format: Yongchang Zhang, Fang Wu, Nong Yang. NHWD-870, a novel BET family bromodomain inhibitor targeting BRD4, proved to be effective and promising for treatment of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1668.
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