Abstract 1190: Discovery of novel compounds selectively targeting LIN28 to modulate let-7 expression and exhibit anticancer activity in LIN28 positive tumors

Abstract The discovery of the highly conserved microRNA (miRNA) lethal-7 (let-7) has increased interest in miRNAs as gene expression regulators. Let-7 suppresses tumor proliferation and survival by downregulating oncogenes and key regulators of the cell cycle, differentiation, and apoptosis. Let-7 is regulated by the RNA-binding protein LIN28, which has an oncofetal expression pattern. Let-7 family members are efficiently uridylated and suppressed in cancer cells via LIN28 reactivation. Therefore, LIN28 is a promising molecular target for directed inhibition, potentially benefiting a diverse group of aggressive malignancies. Despite various efforts to modulate let-7 expression through LIN28 inhibition, selectively targeting LIN28 has been challenging. Using computational analysis and structure-based drug design, we identified a novel class of candidate compounds that exhibited selective anticancer effects in LIN28-expressing tumors. In cell viability assays using the JAR choriocarcinoma and PA-1 teratocarcinoma cells expressing LIN28, the candidates showed nanomolar IC50 values. However, they had negligible effects on LIN28-negative MCF7 breast cancer cells and WI-38 normal fibroblast cells. Pharmacodynamic assays revealed that these compounds selectively modulated the let-7 subclasses, let-7b, let-7d, let-7g, let-7l, and miR-98, demonstrating excellent selectivity in targeting LIN28. Western blot analysis further demonstrated effective suppression of cancer stem cell markers, including OCT4, SOX2, and MYC. In vivo studies using LIN28-positive IGROV-1 ovarian cancer xenograft model indicated strong inhibition of tumor growth following intratumoral administration. Pharmacokinetic studies revealed rapid absorption, with >30% bioavailability and a 3-hour half-life with oral administration. However, limited tumor distribution is expected owing to the low volume of distribution in the intravenous pharmacokinetic results, indicating the need for future optimization of the distribution profile. This study highlights promising lead compounds that selectively inhibit LIN28, enhance let-7 expression, thereby reducing cancer hallmarks and exerting anticancer effects. Future efforts should focus on optimizing the pharmacokinetic profile to develop an orally bioavailable LIN28 inhibitor for effective cancer treatment. Citation Format: Myongjae Lee, Minkyung Kim, Jong Ha Kim, Sung Wook Kwon, Won Sik Lee. Discovery of novel compounds selectively targeting LIN28 to modulate let-7 expression and exhibit anticancer activity in LIN28 positive tumors [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 1190.