Abstract 4483: New drug development opportunities for PARP1

Abstract

Abstract Personalized therapies allow, not only the increase of its therapeutic efficiency, but also the reduction of the secondary effects associated to the treatment of cancer. Data obtained in our group suggest that PARP1 could play a key role in the cell cycle regulation through its interaction with E2F1 transcription factor. Considering that most oncogenic processes is associated with cell cycle deregulation, the disruption of this interaction would provide a new therapeutic target of great interest and wide spectrum of indications. Therefore, our goal was to find molecules that interfere its role in cell-cycle regulation without affecting its function on DNA repair. The identification of novel compounds disrupting the PARP1/E2F1 interaction was carried out by combining in silico and in vitro screening, using a rational drug design. The virtual screen was performed using a molecular library of several million compounds at the selected target site, using AtomNet® (Atomwise), the first deep learning neural network for structure-based drug design and discovery. Since there is no complete structural information of the PARP-1/E2F1 protein-protein interaction, a homologous structure of BRCT domain of BRCA1 complex with the phospho-peptide (PDBID: 1T2V) was utilized to identify the potential binding interface of BRCT domain of PARP-1 (PDBID: 2COK) and the E2F1 protein. Top scoring compounds were clustered and filtered to arrive at a final subset of 83 compounds, library that were incorporated to our in vitro screening, which included both transcriptional (E2F1 activity) and survival studies. Twelve compounds were finally selected, based upon their higher capacity of inhibiting E2F1 activity.This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Pablo Iglesias, David Moreiras, Laura Porres-Ventin, Lara Gonzalez-Rendo, Jose A. Zumalave, Victor M. Arce, Jose A. Costoya. New drug development opportunities for PARP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4483.