Abstract P4-08-30: Preclinical Characterization and Safety of First-in-Class, brain penetrant ALC1 Inhibitor EIS-12656 in HRD cancers

Abstract EIS-12656, a first-in-class ALC1 inhibitor, has shown promising antitumor activity in preclinical studies, aimed at effective cancer management. Our inhibitor specifically targets ALC1, a crucial chromatin remodeler activated by PARP within the DNA damage response (DDR) context. This study focuses on the comprehensive preclinical characterization and safety evaluation of EIS-12656, currently in a Phase I/II clinical trial. Biochemically, EIS-12656 is an allosteric, activation dependent inhibitor of ALC1. Its inhibition results in the trapping of ALC1 alongside PARP1 and PARP2 at sites of DNA damage. EIS-12656 demonstrated selective cytotoxicity against multiple human cancer cell lines deficient in homologous recombination, with IC50 values in the nanomolar range. This selective targeting of PARP1, PARP2, and ALC1 at sites of DNA damage resulted in G2/M arrest. In vivo studies indicated that EIS-12656 has monotherapy efficacy outcompeting best in class PARP inhibitors. EIS-12656 is well-tolerated at doses up to 1.000mg/kg in both rodent and non-rodent species and displays no significant adverse effects on body weight, food consumption, or clinical observations. Hematological and clinical chemistry analyses revealed no deviations from normal ranges. Histopathological examinations showed no drug-related toxicities. EIS-12656 is well absorbed, distributed, brain penetrant and accumulates in the tumor. Pharmacokinetic analysis indicated dose-proportional exposure and a half-life suitable for once-daily oral administration, providing a strong rationale for the currently recruiting Phase I/II clinical trial to further assess EIS-12656’s safety and efficacy in biomarker selected oncology patients. Citation Format: Adrian Schomburg, William Menzer, Markus Lechner, Gunnar Knobloch, Katharina Sahiri, Xin Zhang, Andreas Ladurner. Preclinical Characterization and Safety of First-in-Class, brain penetrant ALC1 Inhibitor EIS-12656 in HRD cancers [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-30.