Abstract

Abstract Epigenetic modulators have emerged as potent therapeutic agents for treatment of patients with cancers. We have developed dual-function small molecules targeting activation of ATM, the DNA damage response transducer, ataxia telangiectasia mutated gene product, and inhibition of histone deacetylases (HDACi). The goal is to develop a single-molecule therapeutic that optimizes the protective effects of ATM activation in normal tissue while targeting HDAC inhibition to sensitize cancerous tissue to radiation. The candidate compound SP-1-161 is a hydroxamic acid that was rationally designed by optimizing ATM activation in the cap domain. In vitro assays against a panel of Class I and Class II HDAC enzymes identified SP-1-161 as a pan-HDAC inhibitor with nanomolar potency (IC50 = 8 nM). Western analysis confirms that SP-1-161 increases acetylated histone H3/H4 and α-tubulin and activates ATM (p-ATM/S1987) in MCF7 cells. The cytotoxicity values (IC50) were in low micro-molar ranges in normal breast epithelial (184A1) and breast cancer (MCF7) cell lines. Radiation clonogenic survival assays demonstrated that the compound protected nonmalignant 184A1 cells (from D0 = 1 Gy to D0 =1.4 Gy) while increasing sensitivity of malignant MCF7 cells to IR (from D0=1.6 Gy to D0=1.12 Gy). Furthermore, in vivo plasma pharmacokinetics following oral administration revealed the area under the curve of 415.79 ng/ml × h with the half-life 1.94 h. Together, our results demonstrate that SP-1-161 is an unprecedented radiation chemotherapeutic agent for treating cancers and protecting normal cells, potentially by targeting the DDR signaling pathways. Citation Format: Scott Grindrod, Alfredo Velena, Mira Jung. Targeting the ATM-mediated DNA damage response pathway for cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A178.

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