Abstract 1642: Next trip: a promising CK1α-selective molecular glue degrader in MSS colorectal cancer

Abstract Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a critical role in cellular homeostasis. In previous studies, CK1α promotes p53 inactivation by regulating MDM2 and MDMX, and this mechanism may represent a promising anticancer target Indeed, many studies have been reported recently on the development of CK1α inhibitors and degraders as anticancer agents. We recently developed PIN5018, a selective CK1α inhibitor, and reported that it exhibits promising anticancer activity in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Interestingly, PIN5018 showed anti-tumor activities in aggressive subtypes of AML patient xenograft (PDX) and ACC patient-derived xenograft (PDX) model. Strikingly, our CK1α MGD not only achieved complete remission in the ACC PDX model during drug administration but also maintained this effect for more than 20 days after discontinuation of the treatment. We conducted 2D or 3D in vitro activity assessments to screen for anticancer activity in additional candidate solid tumors. Based on these results, we focused our research on colorectal cancer (CRC). CRC is the third most prevalent cancer and a leading cause of cancer-related deaths worldwide. Over 80% of CRC patients are of the microsatellite stable (MSS) type, which, unlike the MSI group, represents a population with high unmet needs. For example, while chemotherapy and certain targeted therapies are available, they are applicable to only a subset of MSS patients, resulting in limited treatment options. From this perspective, we aimed to investigate the correlation between specific biomarkers and the in vitro and in vivo efficacy of PIN5018 in MSS CRC. As a result, we identified promising anticancer efficacy of PIN5018-mediated CK1α degradation under specific combinations of biomarker mutation conditions. Furthermore, we observed synergistic effects with PIN5018 when combined with standard of care (SoC) drugs. Taken together, these findings demonstrate the potential of our CK1α-selective MGD as a promising therapeutic candidate not only for AML and ACC but also for MSS CRC. Lastly, we are aiming for clinical entry by 2025 Q1. Citation Format: Hyunsun Jo, Hoon Choi, Hyemin Kim, Sohyun Park, Yelim Shin, Hyewon Shin, Yeonju Yoo, Dohee Yoon, Cheongbi Kim, Jinuk Kong, Goun Choi, Hadong Kim. Next trip: a promising CK1α-selective molecular glue degrader in MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1642.