2021 - BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies
Patchliner Publication in Journal of Medicinal Chemistry (2021)
Authors:
Berger M., Wortmann L., Buchgraber P., Lücking U., Zitzmann-Kolbe S., Wengner A.M., Bader B., Bömer U., Briem H., Eis K., Rehwinkel H., Bartels F., Moosmayer D., Eberspächer U., Lienau P., Hammer S., Schatz C.A., Wang Q., Wang Q., Mumberg D., Nising C.F., Siemeister G.
Journal:
Journal of Medicinal Chemistry (2021) doi: 10.1021/acs.jmedchem.1c00762
Abstract:
Eukaryotes have evolved two major pathways to repair potentially lethal DNA double-strand breaks. Homologous recombination represents a precise, DNA-template-based mechanism available during the S and G2 cell cycle phase, whereas non-homologous end joining, which requires DNA-dependent protein kinase (DNA-PK), allows for fast, cell cycle-independent but less accurate DNA repair. Here, we report the discovery of BAY-8400, a novel selective inhibitor of DNA-PK. Starting from a triazoloquinoxaline, which had been identified as a hit from a screen for ataxia telangiectasia and Rad3-related protein (ATR) inhibitors with inhibitory activity against ATR, ATM, and DNA-PK, lead optimization efforts focusing on potency and selectivity led to the discovery of BAY-8400. In in vitro studies, BAY-8400 showed synergistic activity of DNA-PK inhibition with DNA damage-inducing targeted alpha therapy. Combination of PSMA-targeted thorium-227 conjugate BAY 2315497 treatment of human prostate tumor-bearing mice with BAY-8400 oral treatment increased antitumor efficacy, as compared to PSMA-targeted thorium-227 conjugate monotherapy.