Presentation Information
[P01-109]Development of Selective Small-Molecule Modulators of PARP14 Through Rational Design and Biochemical Screening
○Stephanie S Schweiker1, Stephan M Levonis1 (1. Bond University (Australia))
Keywords:
PARP14 inhibition,small-molecule drug design,chemical biotechnology,cancer chemosensitisation,cisplatin combination therapy
[Purpose]
Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that regulate DNA repair and cellular survival pathways. Dysregulation and overexpression of PARP1 and PARP14 have been associated with multiple malignancies. Although several PARP1 inhibitors have been developed for clinical use, many lack selectivity across the PARP enzyme family, and no clinically approved inhibitors specifically targeting PARP14 are currently available. The development of structurally diverse small-molecule libraries is therefore required to identify selective modulators of PARP catalytic activity and to expand the available chemical tools for probing PARP biology.
[Method]
A series of novel small-molecule analogues were designed based on a generalised scaffold to explore chemical space around the PARP catalytic domain. The compounds were synthesised and screened for inhibitory activity against PARP1 and PARP14 using chemiluminescent in vitro PARP activity assays. Compounds demonstrating promising inhibition profiles were further evaluated for selectivity against additional PARP family members, including PARP2, PARP3, PARP5a, PARP7, and PARP15. To assess the biological relevance of enzyme inhibition, in vitro cell viability assays were performed in cancer cell models treated with lead inhibitors in combination with the chemotherapeutic agent cisplatin.
[Results]
Screening of the synthesised compound library identified two lead compounds demonstrating preferential inhibition of either PARP14 or PARP1 relative to other PARP enzymes. Subsequent cellular studies revealed that treatment with either lead inhibitor in combination with cisplatin significantly reduced cell survival compared with cisplatin treatment alone. At a concentration of 10 µM, the combination treatment produced greater reductions in cell viability, particularly in HeLa and PC-3 cell lines, following 96 hours of exposure.
[Consideration and Conclusion]
This study demonstrates a chemical biotechnology strategy for the discovery of selective PARP inhibitors through the design, synthesis, and biochemical evaluation of structurally diverse small-molecule analogues. Application of the lead compounds in combination with cisplatin in cervical and prostate cancer cell models resulted in significantly reduced cell survival compared with cisplatin alone. These findings suggest that inhibition of PARP enzymes can chemically sensitise cancer cells to DNA-damaging agents, potentially enabling lower effective doses of chemotherapeutic drugs while maintaining cytotoxic efficacy. The results highlight the value of rationally designed chemical libraries as tools for modulating PARP activity and support further development of selective PARP14 inhibitors for therapeutic and chemical biology applications.
[Reference]
Kam, C. M. T., Tauber, A. L., Zunk, M. S., McDermott, C. M., Levonis, S. M., & Schweiker, S. S. (2025). Novel inhibitors of PARP1 and PARP14: design, synthesis, and potentiation of cisplatin efficacy in cancer. Future Medicinal Chemistry, 17(1), 35–58. https://doi.org/10.1080/17568919.2024.2437972
Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that regulate DNA repair and cellular survival pathways. Dysregulation and overexpression of PARP1 and PARP14 have been associated with multiple malignancies. Although several PARP1 inhibitors have been developed for clinical use, many lack selectivity across the PARP enzyme family, and no clinically approved inhibitors specifically targeting PARP14 are currently available. The development of structurally diverse small-molecule libraries is therefore required to identify selective modulators of PARP catalytic activity and to expand the available chemical tools for probing PARP biology.
[Method]
A series of novel small-molecule analogues were designed based on a generalised scaffold to explore chemical space around the PARP catalytic domain. The compounds were synthesised and screened for inhibitory activity against PARP1 and PARP14 using chemiluminescent in vitro PARP activity assays. Compounds demonstrating promising inhibition profiles were further evaluated for selectivity against additional PARP family members, including PARP2, PARP3, PARP5a, PARP7, and PARP15. To assess the biological relevance of enzyme inhibition, in vitro cell viability assays were performed in cancer cell models treated with lead inhibitors in combination with the chemotherapeutic agent cisplatin.
[Results]
Screening of the synthesised compound library identified two lead compounds demonstrating preferential inhibition of either PARP14 or PARP1 relative to other PARP enzymes. Subsequent cellular studies revealed that treatment with either lead inhibitor in combination with cisplatin significantly reduced cell survival compared with cisplatin treatment alone. At a concentration of 10 µM, the combination treatment produced greater reductions in cell viability, particularly in HeLa and PC-3 cell lines, following 96 hours of exposure.
[Consideration and Conclusion]
This study demonstrates a chemical biotechnology strategy for the discovery of selective PARP inhibitors through the design, synthesis, and biochemical evaluation of structurally diverse small-molecule analogues. Application of the lead compounds in combination with cisplatin in cervical and prostate cancer cell models resulted in significantly reduced cell survival compared with cisplatin alone. These findings suggest that inhibition of PARP enzymes can chemically sensitise cancer cells to DNA-damaging agents, potentially enabling lower effective doses of chemotherapeutic drugs while maintaining cytotoxic efficacy. The results highlight the value of rationally designed chemical libraries as tools for modulating PARP activity and support further development of selective PARP14 inhibitors for therapeutic and chemical biology applications.
[Reference]
Kam, C. M. T., Tauber, A. L., Zunk, M. S., McDermott, C. M., Levonis, S. M., & Schweiker, S. S. (2025). Novel inhibitors of PARP1 and PARP14: design, synthesis, and potentiation of cisplatin efficacy in cancer. Future Medicinal Chemistry, 17(1), 35–58. https://doi.org/10.1080/17568919.2024.2437972
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