Abstract
PARP1 is a key DNA damage response enzyme that supports tumor-cell survival through PARP-mediated DNA repair. Although FDA-approved PARP inhibitors have validated this therapeutic strategy, limited PARP1/PARP2 selectivity may cause adverse effects. This patent discloses next-generation PARP1 inhibitors with improved potency, selectivity, and brain-penetrant pharmacokinetic properties.
Important Compound Classes
Title
PARP1 inhibitors and uses thereof
Patent Publication Number
WO 2025/090418 Α1, URL: https://patents.google.com/patent/WO2025090418A1/en
Publication Date
May 1, 2025
Priority Application
US 63/592, 458
Priority Date
October 23, 2023
Inventors
Hoffman, R. L.; Mish, M. R.; Taylor, J. G.
Assignee Company
Gilead Sciences, Inc. [US/US]; 333 Lakeside Drive, Foster City, California 94404, United States.
Disease Area
Cancers
Biological Target
PARP1
Summary
Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involving DNA damage response, responsible for recognizing DNA strand breaks and catalysis of poly(ADP-ribosyl)ation, play a crucial role in facilitating the recruitment and regulation of DNA repair. Rapid tumor cell proliferation frequently leads to accumulated DNA damage, rendering malignant cells highly dependent on homologous recombination and PARP-mediated DNA repair pathways for survival. Pharmacological inhibition of PARP has emerged as a clinically validated anticancer strategy, particularly for tumors harboring homologous recombination deficiency, particularly BRCA1/2 mutant malignancies. Although multiple FDA-approved PARP inhibitors have demonstrated clinical efficacy and established PARP inhibition as a viable therapeutic modality, many currently available agents exhibit limited selectivity among PARP family members, particularly between PARP1 and PARP2. This selectivity issue is therapeutically significant, as PARP1 inhibition is generally regarded as the primary contributor to antitumor activity, whereas concomitant PARP2 inhibition may be associated with hematologic toxicity and other dose-limiting adverse effects. Therefore, the development of next-generation PARP inhibitors with enhanced PARP1 potency, improved PARP1/PARP2 selectivity and ability of the blood–brain barrier (BBB) remains an important objective, especially for therapeutically challenging indications such as brain tumors. On this basis, the present patent application discloses a series of PARP1 inhibitors designed to achieve potent PARP1 inhibition while improving PAPR1 selectivity and brain penetration.
Definitions
R1 = C1–C4 alkyl, C3–C6 cycloalkyl, fluoroalkyl, difluoroalkyl, cyanoalkyl;
L = azetidinyl, pyrrolidinyl, pyrrolidin-3-yloxy, 2-methylazetidin-3-yloxy;
X = O or none; Y = CH2 or none; Z = N or CH
Key Structures
Biological Assay
The biochemical PARP1/PARP2 inhibition assay was using a commercial fluorescence-based assay platform. This assay directly measures whether the compounds inhibit PARP1 and PARP2 enzymatic activity, allowing calculation of PARP1 IC50, PARP2 IC50, and therefore PARP1/PARP2 selectivity.
Biological Data
The table below displayed the IC50 value against PARP1 and PARP2 for selected examples.
Claims
Total claims: 7
Compound claims: 1
Pharmaceutical composition claims: 1
Method claims: 5
Recent Review Articles
See refs − .
Recent Research Articles
See refs , .
This highlight was partially supported by the NIH grant (AG094161).
The authors declare no competing financial interest.
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