DNA dependent protein kinase (DNA-PK) is a serine/threonine protein kinase composed of catalytic subunits (DNA-PKcs) and Ku heterodimers composed of Ku70 and Ku80 subunits. Specifically, DNA-PK plays an important role in cellular DNA damage response (DDR). Besides, DNA-PK phosphorylates Sp1 during the formation of Sp1 transcription complex. DNA-PK has been found to be involved in other cellular processes, including cell cycle progression and telomere maintenance. Moreover, DNA-PKcs are members of the phosphatidylinositol 3-kinase related kinase family and can phosphorylate over 700 substrates. DNA-PK has become an interesting therapeutic target for treating various types of cancer. Furthermore, MTOR plays a core role in regulating many basic cellular processes, from protein synthesis to autophagy. The disordered mTOR signal transduction is related to the progress of cancer and diabetes and the aging process. Today, we will introduce a dual DNA-PK and mTOR kinase inhibitor for various cancers research, CC-115.
CC-115 is a Dual DNA-PK and mTOR Kinase Inhibitor for Various Cancers Research.
To begin with, CC-115 is a potent and dual DNA-PK and mTOR kinase inhibitor with IC50s of 13 nM and 21 nM, respectively. Meanwhile, CC-115 blocks both mTORC1 and mTORC2 signaling.
Secondly, CC-115 inhibits PC-3 cells proliferation with an IC50 of 138 nM. Of the PI3K related kinases (PIKKs) tested, CC-115 proves to be equipotent against DNA PK (IC50=15 nM). Importantly, CC-115 demonstrates 40 to >1000 fold selectivity against the remaining PIKKs tested.
Taken together, CC-115 shows good in vivo PK profiles across multiple species with 53%, 76% and ~100% oral bioavailability in mouse, rat and dog, respectively. Particularly, CC-115 is tested at lower doses of 0.25, 0.5 and 1 mg/kg bid or 1 mg/kg qd, with observed corresponding tumor volume reductions of 46%, 57%, 66% and 57% respectively.
All in all, CC-115 is a dual DNA-PK and mTOR kinase inhibitor for various cancers research.
References:
Mortensen DS, et al. J Med Chem. 2015 Jul 23;58(14):5599-5608.