Abstract 5719: Identification of EIK1004 (IMP1707), a CNS-penetrant, potent, and selective PARP1 inhibitor poised for testing in patients with HRD mutant tumors

Abstract INTRODUCTION: Nonselective poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be effective in patients whose tumors harbor mutations in DNA repair proteins, although their efficacy is hampered by dose reductions and suspensions due to on-target toxicity resulting from PARP2-related hematologic suppression. Currently available PARP inhibitors have limited brain penetrance, limiting their utility for central nervous system (CNS) tumors or brain metastases. PARP1 inhibition alone can result in an antitumor effect similar to pan-PARP inhibition; therefore, development of PARP1-selective inhibitors with broad selectivity over PARP2 and brain penetrance is desirable. EIK1004 (previously IMP1707) is a potent, CNS-penetrant, PARP1-selective molecule with robust pharmaceutical properties. METHODS: Inhibitory activity of EIK1004 was measured using recombinant PARP1 and PARP2 proteins in an in vitro PARylation assay and separately in an in vitro PARP trapping assay. Antiproliferative potential was measured in cell-based 7-day growth assays utilizing MDA-MB-436 (triple negative breast cancer, BRCA1 mutant), DLD1 (colorectal, BRCA2 knockout [KO]), and parental cell lines. In vivo antitumor effects were assessed in MDA-MB-436 and DLD1 KO subcutaneous xenograft models grown in NOD/SCID and nude mice, respectively. Brain penetrance and CNS antitumor activity were evaluated using an MDA-MB-436-luc intracranial xenograft model, and target engagement was measured in tumors using Western blot analysis to assess total PAR levels. RESULTS: EIK1004 potently and selectively inhibits PARP1 enzyme (IC50 < 1 nM) with > 800-fold selectivity over PARP2, and potently traps PARP1 on DNA (IC50 < 1 nM). As a result of PARP1 inhibition and trapping, EIK1004 inhibits the growth of homologous recombination deficient (HRD) cell lines with potencies of < 5 nM, while having no effect on the growth of cells with intact DNA repair mechanisms. The antitumor activity of EIK1004 was tested in mouse xenograft models. In MDA-MB-436 and DLD1 BRCA2 KO xenograft models, oral EIK1004 administered once daily at doses ≤ 1 mg/kg led to significant, dose-dependent tumor regression in these 2 models, respectively. In the MDA-MB-436-luc intracranial xenograft model, EIK1004 was shown to result in robust tumor regression at doses ≤ 1 mg/kg daily. In this model, total PAR levels in the tumor were shown to be significantly reduced (∼90%) at all dose levels tested. CONCLUSION: EIK1004 potently and selectively inhibits and traps PARP1, with downstream activity in cells and mouse models. EIK1004 exhibits robust pharmacokinetic properties including brain penetration, high bioavailability across preclinical species, and a safety profile that supports further development. EIK1004 is currently being evaluated in a Phase 1 clinical trial in solid tumors with or without brain metastasis. Citation Format: Melissa Dumble, Ye Edward Tian, Ali Tabatabaei, Brenda Smith, Viola J. Chen, Ning Ma, Xiaozhu Wang, Yuxiao Zhao, Ruiyu Zhou, Yangzhen Jiang, Mu Chen, Sui Xiong Cai. Identification of EIK1004 (IMP1707), a CNS-penetrant, potent, and selective PARP1 inhibitor poised for testing in patients with HRD mutant tumors [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 5719.