Abstract 1244: Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action

Abstract

Abstract Introduction: Cancer is a leading cause of death worldwide, as about 1 in 6 deaths is due to cancer. Despite the advances in cancer treatment, the success rate of cancer cure is very low, due to the low therapeutic index and many off target side effects of the available anticancer drugs. This highlight the urgent need for the development of novel anticancer compounds with high efficacy and wide safety margin. Methods: Phenotypic screening of a skeletally diverse library of benzopyrane yielded a unique chemotype with novel anticancer mechanism. Cell viability assays were performed against a panel of cancer cell lines followed by various assays to verify the effect of our compound on inducing apoptosis, DNA damage, cell cycle arrest. For further explore the compound's mechanism of action, a proteomic study was conducted along with western blot analysis, metabolism studies and other enzymes specific mechanistic assays. In addition, mouse tumor model was developed to assess the safety and the activity of the compound in vivo. Results: The novel compound possesses a potent anticancer effect against multiple cancer cell lines, induces apoptosis, DNA damage and perturbs the cell cycle progression. Interestingly, it inhibits the activity of essential enzymes involved in the cell's redox balance including Thioredoxin and Glutathione reductases. Moreover, it inactivates vital cancer survival pathways. Lastly, the compound safely reduces tumor proliferation in vivo. Conclusion: Due to the achieved safety profile, potency and efficacy of this novel benzopyrane derived agent as well as its unique mechanism of action, the compound is a potential candidate for further testing in preclinical and clinical settings. Keywords: Multitarget, apoptosis, DNA damage, cell cycle, thioredoxin reductase, glutathione reductase Citation Format: Dana Zaher, Wafaa Ramadan, Raafat El-Awady, Hany Omar, Fatema Hersi, Vunnam Srinivasulu, Taleb Al-Tel. Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1244.