Abstract 3041: Arsenoplatin-5: A small molecule that delivers arsenous acid

Abstract Arsenic trioxide (ATO), an FDA-approved drug for treating Acute Promyelocytic Leukemia (APL), increased the survival of newly diagnosed and relapsed APL patients. Despite its success in treating blood cancer, this success did not translate in clinical trials treating solid tumors due to low bioavailability, rapid renal clearance, and cardiotoxicity when higher doses are applied. The search for agents that deliver ATO to solid tumors has been ongoing for almost two decades. While a number of nanoformulations have been evaluated, none have been approved for clinical use. Our solution to this problem is developing small molecules that release arsenous acid, the aqueous and active form of ATO. Inspired by the synergy between cisplatin and ATO, we designed arsenoplatins, dual pharmacophore agents in which an aqueous form of arsenic(III) is covalently bound to the platinum(II) center. Given superior arsenoplatin-5 (AP-5) activity against TNBC (triple-negative breast cancer) cell lines relative to cisplatin or ATO used as single drugs, its potency was evaluated in a five-dose NCI-60 screen using the Sulforhodamine B (SRB) assay by Developmental Therapeutics Program at the National Cancer Institute (DTP-NCI). The COMPARE algorithm was used to compare GI50, TGI, and LC50 values, thereby allowing evaluation of the inhibitory and cytotoxic activity of AP-5 to all other agents in the NCI database. A very high Pearson correlation coefficient (PCC) of 0.84 is obtained when AP-5’s GI50 values were compared to GI50 values of ATO, indicating a similar mechanism of action. The uptake of AP-5 was evaluated in TNBC MDA-MB-231 cells using ICP-MS (inductively coupled plasma mass spectrometry). Significantly more arsenic atoms than platinum atoms in cells were taken up upon incubation of MDA-MB-231 cells with 10 µM AP-5. These results are consistent with a model in which the Pt-As bond in AP-5 breaks inside the cell and releases arsenous acid moiety, with arsenic being more retained in cells than platinum, in correlation with high PCC revealed. Interestingly, when comparing LC50 values of AP-5 with all other agents in the NCI database using a COMPARE algorithm, the highest PCC was obtained for alkylating agents, pipobroman and cisplatin (0.47 and 0.46, respectively). These results support a dual mechanism for arsenoplatins wherein the inhibitory activity of AP-5 is due to arsenic pharmacophore and cytotoxic activity due to platinum pharmacophore. Remarkably, although bearing both platinum and arsenic pharmacophores, AP-5 is significantly less toxic than cisplatin, based on single maximum tolerated dose (MTD) studies in vivo in female C57BL/6 mice. These results demonstrate that AP-5 is a potent, well-tolerated dual pharmacophore agent in vivo and represents the first small molecule capable of delivering an aqueous form of arsenic(III). Citation Format: Denana Miodragovic, Wenan Qiang, Bong Jin Hong, Thomas O'Halloran. Arsenoplatin-5: A small molecule that delivers arsenous acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3041.