Abstract 1726: Preclinical development of APL-045: A selective PERK inhibitor targeting ER stress pathways in cancer

Abstract The unfolded protein response (UPR) is a critical component of the integrated stress response (ISR) pathway, activated in response to the accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER). A key mediator in this pathway is protein kinase RNA-like ER kinase (PERK), which becomes active under conditions of ER stress. Upon activation, PERK phosphorylates eIF2α, temporarily halting general protein translation to reduce the burden on the ER. Cancer cells can exploit PERK signalling to enhance their survival and proliferation under stress, leveraging this pathway to adapt to UPR triggered by hypoxic, nutrient-deprived tumour microenvironments, or as a response to anticancer therapies. Inhibition of PERK is therefore a promising therapeutic target in oncology. APL-045 is a novel, selective, ATP-competitive inhibitor of PERK. APL-045 demonstrated potent inhibition of PERK, with a Ki of 4.6 nM and IC50 for eIF2α phosphorylation inhibition of 20 nM. Selectivity screening showed high specificity, with very limited off-target effects among 468 kinases tested in a Kinome Scan®. In vitro studies demonstrated that APL-045 effectively inhibited downstream effectors of the PERK-mediated UPR pathway, ATF4 and CHOP, in a dose-dependent manner with the IC50 values ranged from 50 to 250 nM across renal cell carcinoma (RCC) and colorectal cancer cell lines. In vivo, APL-045 significantly reduced tumour volume in 786-O RCC xenograft models, achieving over 95% tumour growth inhibition after three weeks of treatment. These findings underscore the potential of APL-045 as a promising therapeutic candidate for cancers driven by PERK-dependent pathways. APL-045 has a highly favourable pharmacokinetic profile, with good solubility, high permeability, and robust metabolic stability in both microsomal and hepatic assays in rodent, dog and human in vitro systems. These properties have translated to high bioavailability. This favourable profile is projected to represent a best-in-class PERK inhibitor. These data describe the efficacy and drug-like properties of APL-045, a candidate stage, best-in-class PERK inhibitor poised to progress into IND-enabling and clinical studies. Citation Format: Krishna Kolluri, Clara Stead, Susanne Wright, Paul Glossop, Emmanuel Demont, Richard Butt, Nadine Clemo. Preclinical development of APL-045: A selective PERK inhibitor targeting ER stress pathways in cancer [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 1726.