Abstract 2459: ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity

Abstract ADT-030 is a novel indene identified from a screening campaign and chemically optimized for drug-like properties that acts as a dual inhibitor of RAS and β-catenin signaling. Here we demonstrate that ADT-030 binds RAS with high affinity and inhibits MAPK/AKT signaling with high potency and selectivity in KRAS mutant cells to inhibit proliferation and induce apoptosis. ADT-030 also inhibits phosphodiesterase 10A (PDE10) that is overexpressed in cancer cells to selectively activate cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling, which induces phosphorylation and degradation of the oncogenic pool of β-catenin. ADT-030 exhibited cytotoxicity to a variety of murine cancer cell lines in vitro, and inhibited tumor growth in syngeneic immunocompetent mice when orally administered. The antitumor activity of ADT-030 was diminished in mice that were immunodeficient or depleted of CD8+ T cells, indicating a critical role of the host immune system. In a metastatic breast tumor mouse model (4T1), ADT-030 not only delayed the growth of the primary tumor but also reduced tumor colonization in the lungs, leading to increased survival. CyTOF and scRNAseq analyses provided a plethora of information revealing the impact of ADT-030 on the immune milieu in the tumor microenvironment. Notably, ADT-030 selectively induced apoptosis of myeloid-derived suppressor cells (MDSCs) while CD8+ T cells were not affected. Consequently, ADT-030 treatment resulted in a marked reduction of MDSCs, which was accompanied by increased tumor infiltration of effector CD8+ T cells. ADT-030 treatment of cancer cells led to immunogenic cell death and enhanced dendritic cell activation. Furthermore, the ability of ADT-030 to augment the antitumor activity of immune checkpoint blockade therapy underlines its potential as a desirable immune-potentiating agent to improve the outcome of cancer immunotherapy. ADT-030 represents a development candidate ready for IND-enabling safety assessment. Citation Format: Md Yeashin Gazi, Ogacheko Okoko, Xin Wang, Caitlin Brandle, Xi Chen, Khalda Fadlalla, Adam Keeton, Yulia Maxuitenko, Catherine Hedrick, Huidong Shi, Gary Piazza, Gang Zhou. ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2459.