Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer cells often exhibit supernumerary centrosomes, a deviation from normal cells.
• Tankyrase 1 (TNKS1) and PARP16 are implicated in spindle organization and suppressing multipolar spindles in cells with extra centrosomes.

Purpose of the Study:

• To identify small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors.
• To find compounds that induce a multipolar spindle phenotype by declustering centrosomes in cancer cells.

Main Methods:

• Phenotypic screening of AstraZeneca's phthalazinone PARP inhibitor collection in HeLa cells.
• High-content screening techniques to identify compounds inducing centrosome declustering.
• Characterization of compound activity across a broad panel of PARP family enzyme assays.

Main Results:

• Several phthalazinone PARP inhibitors demonstrated potent activity at low nanomolar concentrations, inducing a multipolar spindle phenotype.
• Identified compounds inhibited multiple PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6.
• Optimization led to AZ0108, a PARP1, 2, 6 inhibitor with potent centrosome clustering inhibition, suitable for in vivo studies.

Conclusions:

• Small molecule PARP inhibitors can effectively induce centrosome declustering and multipolar spindle formation.
• AZ0108 represents a promising drug candidate for further investigation in cancer therapy.
• Targeting centrosome clustering via PARP inhibition offers a novel therapeutic avenue in oncology.