iVeliparib-AP6 is a proteolysis-targeting chimera ( PROTAC ) molecule designed based on Veliparib, which targets PARP1/2. The DC50 s of iVeliparib-AP6 for inducing the degradation of PARP1 and PARP2 are 36 nM and 63 nM, respectively, and its IC50 s are 69 nM and 21 nM, respectively. iVeliparib-AP6 contains a Veliparib -based PARP inhibitor warhead linked to a CRBN E3 ligase binder; it uses Thalidomide as a ligand to recruit CRBN E3 ubiquitin ligase and exerts the PARP2 degradation mechanism [1] [2]. (Pink: PARP-2 and PARP-1 ligand; Blue: Cereblon ligand; Black: linker ).
In Vitro, iVeliparib-AP6 (10 min) inhibits PARP1 and PARP2 catalytic activity in cell-free assays with IC50 values of 69 nM and 21 nM, respectively[1].
References:
[1]. Wang S, et al. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat Chem Biol. 2019;15(12):1223-1231.
[2]. Cao C, et al. Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers. J Med Chem. 2020;63(19):11012-11033.
In Vitro, iVeliparib-AP6 (10 min) inhibits PARP1 and PARP2 catalytic activity in cell-free assays with IC50 values of 69 nM and 21 nM, respectively[1].
References:
[1]. Wang S, et al. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat Chem Biol. 2019;15(12):1223-1231.
[2]. Cao C, et al. Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers. J Med Chem. 2020;63(19):11012-11033.