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

Autor:	Berger M; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Wortmann L; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Buchgraber P; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Lücking U; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Zitzmann-Kolbe S; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Wengner AM; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Bader B; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Bömer U; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Briem H; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Eis K; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Rehwinkel H; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Bartels F; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Moosmayer D; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Eberspächer U; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Lienau P; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Hammer S; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Schatz CA; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Wang Q; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Wang Q; WuXi AppTec (Wuhan) Co., Ltd., 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, P. R. China., Mumberg D; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Nising CF; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany., Siemeister G; Research & Development, Pharmaceuticals, Bayer AG, Berlin 13353, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Sep 09; Vol. 64 (17), pp. 12723-12737. Date of Electronic Publication: 2021 Aug 24.
DOI:	10.1021/acs.jmedchem.1c00762
Abstrakt:	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.
Databáze:	MEDLINE
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