Abstract 3213: IA-05592: A breakthrough oral PD-L1 inhibitor with exceptional anti-tumor efficacy and immune activation potential

Abstract Programmed death-ligand 1 (PD-L1) is a key immune checkpoint protein that interacts with PD-1 on T cells to suppress anti-tumor immunity. While PD-1/PD-L1 antibodies have become a cornerstone of cancer therapy, their limitations, including poor tumor penetration, immunogenicity, immune-related risks due to long half-life, and high production costs, have driven interest in small-molecule alternatives. IA-05592, a novel orally bioavailable small-molecule PD-L1 inhibitor, was developed using structure-based drug design to disrupt PD-1/PD-L1 interactions. This compound offers advantages such as oral bioavailability, reduced costs, and a novel mechanism of action involving PD-L1 internalization and degradation. Biochemical assays using fluorescence resonance energy transfer (FRET) demonstrated IA-05592’s potency in disrupting PD-1/PD-L1 interactions, while cellular activity assays confirmed its ability to activate T cells, with an EC50 of 14 nM in NFAT reporter assays. IA-05592 reduced PD-L1 expression on tumor cells by inducing internalization and degradation, a mechanism confirmed in MC38 cells engineered to express human PD-L1 (MC38-hPD-L1). In vivo, daily oral administration of IA-05592 in a human PD-L1 knock-in MC38 syngeneic mouse model at doses of 10, 30, and 90 mg/kg resulted in dose-dependent tumor reduction. Combination studies with Fingolimod confirmed that IA-05592’s anti-tumor effects are immune-mediated. Pharmacokinetic and ADME studies in rodents revealed high oral bioavailability and systemic exposure, further supporting its therapeutic potential. These findings position IA-05592 as a promising candidate for next-generation cancer immunotherapy, offering a unique mechanism of action and robust preclinical anti-tumor efficacy comparable to anti-PD-L1 antibodies. Ongoing studies aim to advance IA-05592 as a key component of all-oral cancer immunotherapy regimens. Citation Format: Yeo Wool Kang, Ye Eun Kim, Garam Choi, Sol Lee, Deokmo Yang, Jongmin Sung, Kye Jung Shin, Tae-Hwe Heo, Taegwon Oh, Myung Jin Kim. IA-05592: A breakthrough oral PD-L1 inhibitor with exceptional anti-tumor efficacy and immune activation potential [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 3213.