Abstract 4230: Preclinical characterization of ATG-042, a novel MTAP null-selective PRMT5 inhibitor

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Background: Targeting the PRMT5-MTA complex has become a promising strategy for treating MTAPnull cancer in a synthetically lethal manner, avoiding on-target-off-tumor hematological toxicity when using first-generation, non-selective PRMT5 inhibitors. The MTAP gene is deleted in around 10-15% of all human malignancies and the top3 human cancers with the highest frequency of MTAP deletion are GBM, pleural mesothelioma and bladder cancer with high unmet medical need (TCGA data). Herein, we report the preclinical feature of ATG-042, a novel MTAPnull-selective PRMT5 small molecule inhibitor with good brain penetration. Methods: The in vitro activity and MTAP selectivity of ATG-042 on cell proliferation were profiled using HCT116 MTAP wild type (wt) cells, HCT116 MTAP knock out (ko) cells and multiple endogenous MTAPnull cell lines. The in vivo efficacy was tested in cell derived xenograft (CDX) mouse models with HCT116 MTAP wt cells, HCT116 MTAP ko cells, LU99 cells (MTAPnull) and U87MG-luc (MTAPnull). The pharmacokinetic and toxicological properties were assessed with corresponding assay methods. Results: ATG-042 demonstrated potent and selectively inhibitory effect on HCT116 MTAP ko cells’ proliferation (IC50=52nM) and SDMA expression (IC50=0.06nM), but very weak effect on HCT116 MTAP wt cells. Consistently, ATG-042 showed excellent anti-proliferative activities on multiple endogenous MTAPnull cell lines with IC50 values between 10nM and 100nM. ATG-042 demonstrated high permeability (Caco2 assay, A to B, Papp =12.2 x10-6cm/s;ER=0.9), good metabolic stability, and low risk of drug-drug interaction. In vivo PK study shows that ATG-042 is well absorbed, with a dose-dependent increase in plasma distribution and high oral bioavailability in mice, SD rats and beagle dogs. Furthermore, ATG-042 is brain-penetrable (B/P ratio=51% in mice; KPuubrain=0.73 in rats). ATG-042 showed robust in vivo efficacy in both subcutaneous CDX models (HCT116 -MTAP ko, LU99) and orthotopic CDX model (U87MG-luc) as a single agent. In addition, ATG-042 also exhibited the potential in combination with other drugs for antitumor therapy. ATG-042 was well tolerated in both SD rats and beagle dogs after four weeks of continuous administration. Conclusions: In summary, ATG-042 is an oral MTAP null-selective PRMT5 inhibitor with potent efficacy against MTAPnull tumor. It also demonstrated good tolerability and brain penetrability. Citation Format: Ya Kong, Ge Lin, Ming Zhang, Peng Chen, Jay Mei, Bing Hou. Preclinical characterization of ATG-042, a novel MTAP null-selective PRMT5 inhibitor [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 4230.

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