M3814

M3814 is a potent and selective inhibitor of DNA-dependent Protein Kinase (DNA-PK).

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA-PK

Signaling Pathways >> PI3K/Akt/mTOR >> DNA-PK

Research Areas >> Cancer

DNA-PK[1]

In combination with IR, M3814 shows efficacy in all of the 6 mouse models of human cancer. In all models, a dose of 2 Gy administered daily for 1 week in combination with M3814 induces statically significant tumor growth inhibition compare to IR alone. M3814, alone or in combination with IR, does not induce significant weight loss or visual signs of toxicity in the mice in any study[1].

The efficacy of M3814 in combination with IR is evaluated in 6 human xenograft models (HCT116, FaDu, NCI-H460, A549, Capan-1, BxPC3) in mice representing 4 different cancer types (colon, head and neck, lung, and pancreas). Tumor cells are injected s.c. into nude mice, and treatment starts when palpable tumors are established (~100 to 200 mm3 ). M3814 is given orally at different doses (25 to 300 mg/kg) 10 min prior to IR. IR is applied using a radiation therapy device for small rodents calibrated to deliver 2 Gy. Autophosphorylation of DNA-PK (serine2056 ) in FaDu tumor lysates is measured by immunoassay to assess pharmacological inhibition by M3814[1].

[1]. L. Damstrup, et al. M3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), Potentiates the Effect of Ionizing Radiation (IR) in Xenotransplanted Tumors in Nude Mice. IJROBP. 2016; 94, 940-941.

[2]. Frank T. Zenke, et al. Abstract 1658: M3814, a novel investigational DNA-PK inhibitor: enhancing the effect of fractionated radiotherapy leading to complete regression of tumors in mice. AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1658.

Wortmannin | NU7441 (KU-57788) | LY3023414 | Torin 2 | NU7026 | PIK-75 HCl | CC-115 | LTURM 34 | SF2523 | PIK-90 | Compound 401 | YU238259 | VX-984