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Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models.
Zenke, Frank T; Zimmermann, Astrid; Sirrenberg, Christian; Dahmen, Heike; Kirkin, Vladimir; Pehl, Ulrich; Grombacher, Thomas; Wilm, Claudia; Fuchss, Thomas; Amendt, Christiane; Vassilev, Lyubomir T; Blaukat, Andree.
Affiliation
  • Zenke FT; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany. frank.zenke@merckgroup.com.
  • Zimmermann A; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
  • Sirrenberg C; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
  • Dahmen H; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
  • Kirkin V; The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Sutton, London, United Kingdom.
  • Pehl U; Merck KGaA, Biopharma R&D, Discovery Development Technologies, Darmstadt, Germany.
  • Grombacher T; Merck KGaA, Biopharma R&D, Translational Medicine, Darmstadt, Germany.
  • Wilm C; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
  • Fuchss T; Merck KGaA, Biopharma R&D, Discovery Development Technologies, Darmstadt, Germany.
  • Amendt C; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
  • Vassilev LT; EMD Serono Research and Development Institute Inc., Biopharma R&D, Translational Innovation Platform Oncology, Billerica, Massachusetts, United States; a business of Merck KGaA, Darmstadt, Germany.
  • Blaukat A; Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Darmstadt, Germany.
Mol Cancer Ther ; 19(5): 1091-1101, 2020 05.
Article in En | MEDLINE | ID: mdl-32220971
Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridazines / Quinazolines / Radiation, Ionizing / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Carcinoma, Non-Small-Cell Lung / Protein Kinase Inhibitors / DNA-Activated Protein Kinase / Head and Neck Neoplasms Limits: Animals / Female / Humans Language: En Journal: Mol Cancer Ther Journal subject: ANTINEOPLASICOS Year: 2020 Document type: Article Affiliation country: Germany Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridazines / Quinazolines / Radiation, Ionizing / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Carcinoma, Non-Small-Cell Lung / Protein Kinase Inhibitors / DNA-Activated Protein Kinase / Head and Neck Neoplasms Limits: Animals / Female / Humans Language: En Journal: Mol Cancer Ther Journal subject: ANTINEOPLASICOS Year: 2020 Document type: Article Affiliation country: Germany Country of publication: United States