1 research outputs found
Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity
Development of polyÂ(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