AZ9482 is a Triple PARP1/2/6 Inhibitor
Posted On 2021-01-05
PARPs are implicated in a variety of cellular metabolic processes including DNA-damage repair and mitotic spindle formation. In particular, PARP1 is essential in repairing DNA single- and double-strand breaks. For example, PARP1 Inhibitor Olaparib is an effective synthetic lethal strategy in cancer.
Recently, scientists reported a triple PARP1/2/6 inhibitor, AZ0108. It elicits therapeutic effects in breast cancer models in vivo by generating a cytotoxic multipolar spindle phenotype in cancer cells but not in somatic tissue. AZ0108 functions via cellular inhibition of PARP6 MARylation of downstream substrates (checkpoint kinase 1, CHK1. AZ0108 treatment prevents CHK1 MARylation and induces hyperphosphorylation of CHK1, contributing to MPS formation and dysregulation of the cell cycle. However, AZ0108 also displayed toxicity in vivo, the molecular basis of which is currently undefined, limiting pharmacological evaluation of AZ0108.
AZ9482 is a triple PARP1/2/6 inhibitor, with IC50 values of 1 nM, 1 nM, and 640 nM for PARP1, PARP2 and PARP6, respectively.
AZ9482 is a potent MPS-inducing agent discovered via a high-content screen of phthalazinone-based NAD+ mimetics. Additionally, as with all olaparib-like molecules, the AZ9482 phthalazinone core mimics the adenine of NAD+ and is essential for PARP family binding; this moiety retains in our AfBP design, along with the central phenyl ring. During the pharmacokinetic optimization of AZ9482, scientists demonstrated that altering the pyridine group is tolerated in MPS assays. While the 3-nitrile is a key backbone hydrogen bond acceptor, the 5-position represents a convenient point from which to build out into a solvent channel with a small photocrosslinkable clickable moiety.
Ryan T Howard, et al. Structure-Guided Design and In-Cell Target Profiling of a Cell-Active Target Engagement Probe for PARP Inhibitors. ACS Chem Biol. 2020 Feb 21;15(2):325-333.