Abstract 346: Synergistic antiproliferative activity of novel RAD51 inhibitor JKYN-1 and its mesylate salt with standard-of-care cancer drugs

Abstract

Abstract The inherent genetic instability of cancer cells and the dependence of many tumor types on oncogenic drivers contribute selectivity of anticancer agents against tumor cells. That selectivity is limited, and toxicity to normal cells remains a major limitation to the success of chemotherapy. To increase selectivity by exploiting cancer cell genetic instability, we demonstrated that the small molecule IBR2 (an inhibitor of the DNA repair protein RAD51) enhanced cytotoxicity of numerous anticancer drugs including agents that do not directly target DNA (J Pharmacol Expt Ther, 364: 46-54, 2018. doi.org/10.1124/jpet.117.241661). We demonstrated the ability of IBR2 and a derivative [IBR120, (R)-3-(2-(benzylsulfonyl)isoindolin-1-yl)-1h-indole] to synergistically inhibit proliferation of a wider range of cancer cell lines in combination with a broad range of anticancer drugs (Proc. Amer. Assoc. Cancer Res., 60: Abst. 3057, 2019). To improve the activity and potentially increase selectivity for inhibiting RAD51, modifications were made to the structure of IBR120 using a virtual drug-protein docking program, yielding the compound JKYN-1. JKYN-1 inhibits proliferation of cancer cell lines approximately 5 times more strongly than IBR120. Given the potential importance of combining JKYN-1 with targeted anticancer drugs to increase therapeutic index, and the synergy previously observed between IBR120 and agents targeted against specific tumor types, JKYN-1 was tested in combination with targeted agents against a panel of tumor cell lines. Four- to five-day drug exposures were conducted in 96-well plates. Relative cell density determined using vital stains (alamarBlue©, neutral red) was reported as a percent of the fluorescence/absorbance of control cultures. Cell lines were representative of tumors from breast (MCF-7), prostate (DU145, LNCaP), stomach (N87), pancreas (PANC-1, Capan-1, Capan-2) and lung (A549b, H1650). The chemotherapy agents included inhibitors of epidermal growth factor receptor (osimertinib, afatinib), other tyrosine kinases (regorafenib, imatinib), sex steroid receptors (4-OH-tamoxifen, enzalutamide), and microtubule function (docetaxel). To improve solubility, a methylsulfonate salt of JKYN-1 was used for most experiments. JKYN-1-mesylate decreased the concentration of drugs that inhibited proliferation by 50% (IC50) by up to 90%, depending on the drug and cell line, indicating synergy between the agents. There were some combinations in which additivity but no synergy was observed, indicating selectivity for this interaction. Individual combinations will be presented. The ability of JKYN-1 to enhance antiproliferative activity of a wide variety of anticancer agents, and its potential selectivity for cancer cells, make possible the future use of RAD51 inhibitors as systemic therapy potentiators to improve clinical outcomes. Citation Format: Peter J. Ferguson, Mark D. Vincent, Yousef Najajreh, Brian Shilton, Stephen Ritter, Rima Al-awar, Richard Marcellus, Mohammed Mohammed, Methvin Isaac, James Koropatnick. Synergistic antiproliferative activity of novel RAD51 inhibitor JKYN-1 and its mesylate salt with standard-of-care cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 346.