Abstract 416: Development of substituted oxindole derivatives as a Ku-targeted DNA-PK inhibitors for cancer therapy

Abstract

Abstract DNA double strand breaks (DSBs) are the most cytotoxic type of DNA damage. DSB repair pathway deficiency, often observed in cancer cells, results in translocations and genetic mutations that contribute to genomic instability. The generation of DNA DSBs is the primary mechanism of numerous chemo- and radio-therapeutic strategies used to treat various cancers. Modulating DSB repair pathways can have a profound impact on the clinical efficacy of DNA damaging therapies. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a prime role in DSB repair through non-homologous end joining (NHEJ). DNA-PK inhibitors become an attractive therapeutic target for cancer in combination with DSB-inducing radiotherapy and chemotherapy. There are at least 6-7 DNA-PK inhibitors in the preclinical and clinical stages which exhibit potential as treatment for various cancers. However, we have taken a unique and innovative approach to inhibiting DNA-PK via blocking the Ku70/80 heterodimer interaction with DNA, an essential step in DNA-PK activation and phosphorylation activity. Exploiting this unique mechanism of kinase activation, we have expanded our structure-activity relationships of pyrrolone derivatives. Modified synthetic schemes have been developed to allow a series of modifications to the X80 core structure. We have prepared furan, thiophene and pyrrole derivatives that enabled the identification of pharmacophores that impact in vitro potency and cellular off-target toxicity. Towards addressing cellular uptake and bioavailability, we identified substituted oxindole derivatives as potent Ku and DNA-PK inhibitors. These oxindole derivatives exhibited a better cellular uptake while retaining potent Ku inhibitory activity. Our data demonstrate that the cellular effects observed are a function of Ku inhibition and that this novel class of DNA-PK inhibitors can be further developed as anti-cancer therapeutics that can be used as an adjuvant to, or concomitant with radiotherapy and other cancer therapies that induce DNA damage. Citation Format: Dineshsinha Chauhan, Pamela L. Mendoza-Munoz, Narva Deshwar Kushwaha, Hariprasad Aruri, John J. Turchi, Navnath S. Gavande. Development of substituted oxindole derivatives as a Ku-targeted DNA-PK inhibitors for cancer therapy [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 416.