Abstract Colorectal cancer (CRC) is the third most common form of cancer diagnosed in the United States. Standard treatment for CRC utilizes a combination therapy composed of 5-fluorouracil, oxaliplatin, and folinic acid, known as FOLFOX. It has been established that patients with CRC tend to develop drug resistance to FOLFOX leading to a need for new chemotherapeutic treatments. Recent work has established that AS-10, a small molecule established for its promising role in treating pancreatic cancer, to be capable of inhibiting the growth of a range of CRC cell lines, including FOLFOX resistant CRC cells. Twenty-four cyclic and open chain analogs of AS-10 were synthesized and evaluated for their activity in inhibiting the viability of different cancer cells in vitro. The cell viability of these compounds was compared to AS-10 in the cell lines of pancreatic carcinoma (MiaPaCa2), lung carcinoma (H460), colorectal adenocarcinoma (HT29), colorectal carcinoma (HCT116), and FOLFOX resistant HT29 and HCT116 cells. Based on the IC50 values observed from these initial studies, only ASA-7, an open-chain alkyl selenocyanate, could treat all cancer cell lines in a similar concentration range of AS-10. Dose-response curves completed in 6 CRC cell lines indicated IC50 values in the range of 1-2 µM for AS-10 and 3.3-6.6µM for ASA-7. Cell viability evaluation in normal kidney (HEK293T) and colon (FHC) cell lines indicated AS-10 to be less toxic as compared to ASA-7. A similar trend was observed in vivo - AS-10 was 4 times more tolerable in mice as compared to ASA-7. A HCT116 xenograft study demonstrated the ability of AS-10 to significantly inhibit tumor growth in vivo without any apparent systemic toxicity. Moreover, AS-10 was assessed for its ability to act as an acetyl donor for histone acetyltransferase (HAT) and was found to initiate HAT activity in the absence of Acetyl-CoA in pancreatic epithelioid carcinoma (Panc-1) and colorectal carcinoma (HCT116) cells. In conclusion, AS-10 was identified as the best among the 24 analogs, in vitro and in vivo, when treating CRC and found to be capable of inducing HAT activity in both pancreatic and colorectal carcinoma elucidating a possible mechanism of action. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Deepkamal Karelia, Daniel Plano, Shantu Amin, Arun Sharma. Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones [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 6247.