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Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

By Sean W. Reilly (1887607), Laura N. Puentes (5391875), Khadija Wilson (5391878), Chia-Ju Hsieh (389896), Chi-Chang Weng (3813232), Mehran Makvandi (3766129) and Robert H. Mach (279778)

Abstract

Development of poly­(ADP-ribose) polymerase inhibitors (PARPi’s) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi’s also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of <b>10e</b> (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including <b>15b</b> (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi’s can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases

Topics: Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Cancer, Environmental Sciences not elsewhere classified, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, FDA, PARPi, PARP, affinity, Olaparib Framework Shows Reduced DNA Damage, DNA damage
Year: 2018
DOI identifier: 10.1021/acs.jmedchem.8b00576.s002
OAI identifier: oai:figshare.com:article/6515174
Provided by: FigShare
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