Design, Synthesis, and Pharmacodynamic Evaluation of Highly Selective PARP1 Inhibitors with Brain Penetrance

  • J Med Chem. 2025 Jan 23;68(2):1731-1754. doi: 10.1021/acs.jmedchem.4c02463.
Tao Guo  1 ,  Yongting Yuan  1 ,  Yurong Zou  1 ,  Zhongning Guo  1 ,  Tao Yang  1 ,  Minghai Tang  1 ,  Ziyan Ma  1 ,  Zhiyuan Fu  1 ,  Weichen Bo  1 ,  Peng Wang  1 ,  Peng Bai  1 ,  Taijin Wang  2 ,  Tao Jia  2 ,  Jianhong Yang  1 ,  Lijuan Chen  1  2
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
PMID: 39789975 DOI: 10.1021/acs.jmedchem.4c02463
Abstract

Selective poly(ADP-ribose) polymerase 1 (PARP1) inhibitors not only exhibit antitumor efficacy but also offer the potential to mitigate the toxicities typically associated with broader PARP inhibition. In this study, we designed and synthesized a series of small molecules targeting highly selective PARP1 inhibitors. Among these, T26 demonstrated excellent selectivity to PARP1 along with the capability to effectively cross the blood-brain barrier (BBB). T26 exhibited an IC50 of 0.2 nM against PARP1, with a remarkable 610-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC50 of 2.6 nM. T26 also displayed excellent oral bioavailability (F = 87.74%) and long half-life (T1/2 = 76.07 h) in mice, supporting once every Other day administration. Oral administration of T26 at 0.3 mg/kg and 3 mg/kg resulted in significant tumor growth inhibition in both subcutaneous and intracranial xenograft models of MDA-MB-436, suggesting T26 significant potential for the treatment of breast Cancer metastases.

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