Abstract 4251: Drugging of ACOD1 is associated with tumor regression in syngeneic tumor models

Abstract Aconitase decarboxylase 1 (ACOD1, also known as Immune Response Gene or IRG1) is a mitochondrial enzyme responsible for the synthesis of the metabolite itaconate in the TCA cycle of pro-inflammatory macrophages. Utilizing Acod1-/- mice and Acod1 KO cells, recent studies have assigned a cancer-promoting role for ACOD1 and demonstrated its expression in immunosuppressive macrophages, found in the TME of syngeneic tumors (Chen et al, Sci. Adv 2023), and in anti-PD-1 (aPD1)-resistant prostate cells (Schofield et al., Cell Rep 2024). To explore the druggability of ACOD1, we synthesized a series of small MW inhibitors and selected two compounds (ERG344 and its derivative ERG350) for further study. Here, we report that, while both compounds suppress synthesis of itaconate in vitro, ERG350 exhibited a 1000-fold improvement in inhibiting ACOD1 enzymatic activity (IC50 of ∼200 nM) compared to ERG344. Furthermore, both molecules exhibited acceptable pharmacokinetic profiles with half-lives of 8h for ERG344 and 11h for ERG350. Administration of 3 mpk ERG344 as a monotherapy in mice bearing CT26 colon tumors led to complete tumor regression in ∼20% of the animals and partial tumor regression in ∼40% of the animals. Immunophenotyping of ERG344-treated CT26 tumors revealed an increase in the frequency of tumor infiltrating lymphocytes (TILs), especially those expressing the CX3C chemokine receptor 1 (CX3CR1), and an increase in the frequency of mature dendritic cells DC (CD3-CD11b+F4/80-MHCII+CD206-) suggesting that ACOD1 inhibition promotes initiation of an anti-tumor immune response. Increased probability of survival was also observed in the CT26 colon cancer model after daily administration of ERG350 in doses ranging from 0.25 to 3 mpk. The study further reports the effect of ACOD1 inhibition in additional syngeneic models including models of hepatocellular carcinomas Citation Format: Adonia E. Papathanassiu, Weixing Li, Yajie Zhong, Carmen Chak-Lui Wong. Drugging of ACOD1 is associated with tumor regression in syngeneic tumor models [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 4251.