Abstract 5656: Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer

Abstract

Abstract Patients with advanced or metastatic colorectal cancer (CRC) often have poor prognosis and survival. There are ongoing efforts to identify novel molecules to manage advanced and metastatic CRC. Modifications in the quinazoline ring has resulted in effective and clinically approved drugs such as gefitinib, erlotinib, vandetanib among others. We rationalized and synthesized a series of 4-anilinoquinazoline analogues, DW (1-10) and evaluated them for anticancer efficacy in human CRC cell lines (HCT116, HT29, SW620). We identified a lead molecule DW-8, with sub-micromolar potency against CRC lines with selectivity index of DW-8 being >2 folds in CRC cells compared to non-cancerous line, CRL1459. Mechanistically, DW-8 produced significant morphological changes in SW620 cells. This included nuclear condensation, cell shrinkage, blebbing and apoptotic bodies formation which are the hallmarks of apoptosis. We found that the DW-8 induced apoptosis by i) producing cell cycle arrest at G2 phase; ii) activated intrinsic apoptosis as shown by cleaved caspases such as caspase-9, the executioner caspases 3 and 7; iii) produced nuclear fragmentation; and iv) increased the level of reactive oxygen species. We are now synthesizing the analogs of DW-8 and are optimizing the formulations for efficient delivery to CRC tumors in vivo. Overall, our result suggests DW-8 may represent a suitable lead for developing novel compound to treat CRC. Citation Format: Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Yuan Tang, Chandrabose Karthikeyan, Amit K. Tiwari. Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5656.