Abstract LB014: HSK46256, a highly selective and brain penetrable PARP1 inhibitor for the treatment of HRD cancers
Authors: Fan Li, Haisco Pharmaceutical Group, Lei Chen, Yao Li, Qingyuan Meng, Ju Wang, Pangke Yan, Pingming Tang
Journal: Cancer Research (2025)

Abstract It is well known that several PARP inhibitors have been approved for tumors with homologous recombination repair deficiencies (HRD), such as BRCA mutations. However, the common side effect of these inhibitors is hematologic toxicity, which limits their therapeutic index and combination potential with first-line chemotherapies. One possible reason is that all currently approved PARPi are almost equipotent in targeting PARP1 and PARP2. Literature reports suggest that only inhibition of PARP1 is required for anti-proliferative effects and that PARP2 plays a key role in the survival of haematopoietic stem and progenitor cells in animal models. Accordingly, we developed a selective and brain penetrable PARP1 inhibitor that effectively inhibits tumor growth with less hematologic toxicity. HSK46256 is a novel brain penetrant PARPi that potently and selectively inhibits and traps PARP1 with highly selectivity of PARP2. HSK46256 inhibited PARP1 enzymatic activity with a potency (IC50) of 1.04 nM and with greater than 10000-fold selectivity against PARP2. In a cellular PARylation assay using A549 isogeneic cells of PARP1 or PARP2, HSK46256 exhibited a selectivity over 5000-fold of PARP1 vs. PARP2. The CNS penetration of HSK46256 in rodent showed an unbound partition coefficient (Kpuu) of 0.32, indicating good CNS penetration compared to Kpuu of 0.25 of AZD9574. To characterize the preclinical relationship between efficacy, unbound plasma concentrations and PD, a preclinical PK-PD modeling of HSK46256 was employed. We observed a significant and durable PD inhibition of HSK46256 which enable a target IC95 coverage of 40% over the dosing interval to achieve a 100% tumor growth inhibition. Furthermore, in a rat dose range finding study, HSK46526 showed a larger safety window with less toxic findings compared to AZD9574. In summary, HSK46256, a highly selective and CNS penetrable PARP1 inhibitor, exhibits excellent pharmacological and safety properties, and also has the favorable pharmacokinetics profile in preclinical studies. HSK46256 may offer a more efficacious and less toxic cancer treatment compared with currently approved PARPi especially when used in combination with other anti-cancer agents. Furthermore, owing to its CNS penetration capability HSK46256 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases, where HRR suppression or HRD exists or for cancers with high rates of brain metastases. Citation Format: Fan Li, Haisco Pharmaceutical Group, Lei Chen, Yao Li, Qingyuan Meng, Ju Wang, Pangke Yan, Pingming Tang. HSK46256, a highly selective and brain penetrable PARP1 inhibitor for the treatment of HRD cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB014.