Abstract 3716: Discovery of macrocyclic peptides TTA-121 as insulin receptor modulators with anticancer potential: An integrated <i>in-silico</i> and <i>in-vitro</i> investigation

Abstract Insulin receptor (INSR), and Insulin-like growth factor (IGF-1R) are significantly similar to each other, and upon activation by ligands increases cell proliferation, differentiation and metastasis. In addition, for the cancer cells to acquire resistance to existing FDA approved one or downstream of it signaling pathways. So, identification of peptides to participate in the INSR/IGF-1R signaling pathway and possess anticancer is one of the upcoming strategies to treat cancer, and diabetes. In this study, we applied bioinformatics tools to analyze structure-activity relationships (SAR) of chemicals or peptides as insulin receptor (INSR) modulators to identify and gain the molecular insights into structural features responsible for INSR modulators. Later, commercially available cyclic peptide libraries are screened to possess the INSR modulator features, followed by molecular docking simulations/molecular dynamics revealed the binding mode, flexibility, and interacting residues of cyclic peptides which were similar to the binding of insulin-to-insulin receptor. To further validate our in-silico predictions, we conducted an intrinsic fluorescence assay, that demonstrated peptides like TTA-121 changed emission levels like insulin, mimicking insulin function or participating in insulin signaling pathway. Further, we carried out cancer cell proliferation assays in different cancer models like breast, lung and prostate cancer models to validate the potential of chosen peptides as anticancer agents. Our findings establish TTA-121 as a promising anticancer agent. On going studies are aimed to understand further TTA-121, its derivatives and in combination with standard drugs in clinical care are synergistic or additive and elucidating the mechanism of action. Overall, this study highlights the potential of cyclic peptides and its derivatives as INSR modulators and supports their use as standalone treatments or in combination with existing anticancer drugs would ultimately help in development of new cancer therapeutics to benefit cancer care. Citation Format: Veera Chandra Sekhar Reddy Chittepu, Poonam Kalhotra, Tzayhri Osorio-Gallardo, Tzayhri Gallardo-Velazquez, Guillermo Osorio-Revilla. Discovery of macrocyclic peptides TTA-121 as insulin receptor modulators with anticancer potential: An integrated in-silico and in-vitro investigation [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 3716.