Abstract 1654: Discovery of the first-in-class DOT1L PROTAC degrader

The histone methyltransferase, DOT1L is often dysregulated in MLL-rearranged (MLL-r) leukemia, which leads to hyperactivation of MLL target genes and poor prognosis. This dysregulation is particularly common in infants, who are highly vulnerable to treatment-related toxicity. However, current treatment options remain limited, with intensive chemotherapy as the standard approach. Given these circumstances, targeting DOT1L with PROteolysis TArgeting Chimeras (PROTACs) could represent a promising alternative therapeutic strategy. Here, we report the discovery of the first-in-class DOT1L PROTAC degrader, MS2133, which induces DOT1L degradation in a dose- and time-dependent manner via the ubiquitin-proteasome system, without affecting DOT1L mRNA expression. MS2133 shows selectivity for DOT1L over other methyltransferases and effectively inhibits the growth of MLL-r leukemia cells while having no toxic effect on normal cells. Overall, MS2133 is a valuable chemical biology tool for studying DOT1L functions and offers promise as a therapeutic option for MLL-r leukemia treatment. Citation Format: Hyerin Yim, Zhongli Xu, Husnu Kaniskan, Jian Jin. Discovery of the first-in-class DOT1L PROTAC degrader [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 1654.