Abstract B068: Modulation of the DNA damage response by novel Ku-DNA binding inhibitors enhances cellular effects of DNA-double strand break inducing agents

Abstract

The DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) double-strand break (DSB) repair pathway and the DNA damage response (DDR). Consequently, blocking DNA-PK kinase activity is being pursued as a therapeutic strategy for the treatment of cancer in combination with DNA-double strand break inducing agents. We have previously reported the development of Ku-DNA binding inhibitors (Ku-DBi’s) that act via a novel mechanism of action to inhibit DNA-PK catalytic kinase activity by targeting the Ku 70/80 heterodimer interaction with DNA. Ku-DBi’s display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity, and sensitize non-small cell lung cancer (NSCLC) cells to DSB generating therapies bleomycin, etoposide and ionizing radiation. In this study, we have expanded our structure activity relationship analyses to focus on optimizing cellular uptake and reducing protein binding. We present the synthesis and analysis of a new series of Ku-DBi’s which demonstrated that chemical modifications of the X80 core structure can be implemented to achieve these goals while retaining Ku inhibitory activity. Furthermore, novel relationships with in vitro inhibitory activity were identified as a function of new pharmacophore additions. In addition, these novel compounds display reduced non-specific protein binding, increased cellular uptake, and enhanced cellular inhibition on DNA-double strand break repair. These novel compounds enable cellular studies to be conducted in serum contain media and the pursuit of in vivo analysis and represent a significant advance in the development of Ku-DNA binding inhibitors.

Citation Format: Pamela L Mendoza-Munoz, Dineshsinha Chauhan, Navnath S Gavande, John J Turchi. Modulation of the DNA damage response by novel Ku-DNA binding inhibitors enhances cellular effects of DNA-double strand break inducing agents [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B068.