Abstract 6763: KBD111 is a highly selective, long-acting and brain-penetrant PARP1 inhibitor

Abstract Background: Currently, several pan-PARP inhibitors such as olaparib, niraparib, and rucaparib are approved for the treatment of cancers with homologous recombination deficiency (HRD). While these inhibitors have demonstrated significant clinical efficacy, their use is frequently limited by severe toxicities, especially hematological side effects associated with PARP2 inhibition. These adverse effects constrain the potential for combining PARP inhibitors with other anticancer therapies, underscoring the need for selective PARP1 inhibitors. Methods: An enzymatic evaluation was performed to assess the activity and selectivity profile of KBD111 against major PARP family members. Cell proliferation was evaluated in the DLD-1 BRCA2−/− cell line. Pharmacokinetic studies were conducted in mice, rats, and dogs. The antitumor efficacy of KBD111 was investigated in DLD-1 BRCA2−/− and MDA-MB-436-luc mouse xenograft models. Mechanistic analysis revealed that PARP1 activity was reduced in DLD-1 BRCA2−/− tumor-bearing tissues. In addition, hematological toxicity was evaluated in vitro in CD34+ hematopoietic stem cells and in vivo in rats. Results: KBD111 exhibited over 5,000-fold selectivity for PARP2 by DNA-trapping assays, demonstrated potent anti-proliferative activity against BRCA-mutant cancer cell lines, while showing markedly reduced cytotoxicity toward normal CD34+ hematopoietic stem cells (IC50 >10,000 nM) compared to talazoparib (IC50 = 27 nM). In addition, KBD111 exhibited excellent pharmacokinetic properties in different preclinical species and high blood-brain barrier (BBB) permeability. Furthermore, KBD111 achieved superior tumor growth inhibition compared to AZD5305 in DLD-1 BRCA2-/- xenograft models following once every two weeks oral dosing. In an intracranial MDA-MB-436-luc model, KBD111 also demonstrated enhanced efficacy relative to AZD9574 under QW oral dosing. Notably, in vivo studies demonstrated that weekly (QW) treatment exhibited a better safety profile than QD dosing. Moreover, KBD111 was well tolerated in the 14-day toxicity studies in SD rats with 60-fold therapeutic window. Conclusions: KBD111 is a highly potent, long-acting and brain-penetrant PARP1 inhibitor with superior PK properties in different species, supporting its development as a promising candidate for once every two weeks (Q2W) dosing. KBD111 demonstrated much less hematotoxicity than Olaparib and was well-tolerated in 14-day toxicity studies. A Phase 1 trial is planned for 2026. Citation Format: Jing Zhang, Yang Chen, Yonggang Wei, Fei Ye, Zhiyong Li, Xiaoke Liu, Jiannan Cui, . KBD111 is a highly selective, long-acting and brain-penetrant PARP1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6763.