BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies.

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.

• Authors: Markus Berger, Lars Wortmann, Philipp Buchgraber, Ulrich Lücking, Sabine Zitzmann-Kolbe, Antje M Wengner, Benjamin Bader, Ulf Bömer, Hans Briem, Knut Eis, Hartmut Rehwinkel, Florian Bartels, Dieter Moosmayer, Uwe Eberspächer, Philip Lienau, Stefanie Hammer, Christoph A Schatz, Qiuwen Wang, Qi Wang, Dominik Mumberg, Carl F Nising, Gerhard Siemeister
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 17 Pg. 12723-12737 (09 09 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34428039 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• MTOR protein, human
• DNA-Activated Protein Kinase
• PRKDC protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• DNA-Activated Protein Kinase (genetics, metabolism)
• Drug Synergism
• Drug Therapy, Combination
• Gene Expression Regulation (drug effects)
• Hepatocytes (drug effects)
• Humans
• Mice
• Molecular Structure
• Phosphatidylinositol 3-Kinases (genetics)
• Rats
• Structure-Activity Relationship
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Xenograft Model Antitumor Assays