Abstract
The successful use of PARP1 inhibitors like olaparib (Loparza®) in the treatment of BRCA1/2-deficient breast cancer has provided clinical proof-of-concept for applying personalized medicine based on synthetic lethality to the treatment of cancer. Unfortunately, all marketed PARP1 inhibitors act by competing with the cofactor NAD+ and resistance is already developing to this anticancer mechanism. Allosteric PARP1 inhibitors could provide a means of overcoming this resistance. A high throughput screen performed by Tulin et al. identified 5F02 as an allosteric PARP inhibitor that acts by preventing the enzymatic activation of PARP1 by histone H4. 5F02 demonstrated anticancer activity in several cancer cell lines and was more potent than olaparib and synergistic with olaparib in these assays. In the present study, we explored the structure–activity relationship of 5F02 by preparing analogs that possessed structural variation in four regions of the chemical scaffold. Our efforts led to lead molecule 7, which demonstrated potent anti-clonogenic activity against BRCA-deficient NALM6 leukemia cells in culture and a therapeutic index for the BRCA-deficient cells over their BRCA-proficient isogenic counterparts.
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Acknowledgements
The authors would like to thank Dr Furong Sun and the staff at the Mass Spectrometry Lab, School of Chemical Sciences, University of Illinois at Urbana-Champaign for providing the high resolution mass spectrometry data.
Funding
This work was funded by the National Institutes of Health/National Cancer Institute under R01 CA186238 to TS. MT was supported by an Etiuda6 scholarship awarded to her by the Polish National Science Centre.
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EH and MT contributed equally to the paper. EH designed and synthesized the molecules described in the paper and contributed to the preparation of the paper. MT performed pharmacological experiments, prepared figures and contributed to the preparation of the paper. KS-R performed pharmacological experiments. JG performed the in vitro ADME studies. TS oversaw the efforts of MT. WEC supervised the medicinal chemistry efforts, helped design the molecules described in the paper and revised the paper. TS supervised the pharmacology efforts, designed the pharmacology protocols used in the paper and revised the paper. AT contributed to the preparation and revision of the paper.
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All experiments carried out in the course of this work were performed in compliance with OSHA regulations and under protocols that were approved by the Temple University Institutional Biosafety Committee.
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Hewlett, E., Toma, M., Sullivan-Reed, K. et al. Novel allosteric PARP1 inhibitors for the treatment of BRCA-deficient leukemia. Med Chem Res 29, 962–978 (2020). https://doi.org/10.1007/s00044-020-02537-0
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DOI: https://doi.org/10.1007/s00044-020-02537-0