Nevertheless, the scientists discovered, the DNA breaks during HIV integration surprisingly activate DNA-PK, which then performs an unusually destructive role: eliciting a signal that causes the CD4+ T cell to die.
DNA-PK normally coordinates the repair of simultaneous breaks in both strands of molecules that comprise DNA.
It turns out that DNA-PK
is critical to a metabolic process we have been trying to understand for 20 years," said Hei Sook Sul, a professor in UC Berkeley's Department of Nutritional Science and Toxicology and head of the research team behind these new findings.
SF1126, is a proprietary small molecule conjugate containing a pan-PI3K inhibitor that selectively inhibits all PI3K class I isoforms and other key members of the PI3K superfamily, including mTOR, DNA-PK
, PLK-1,CK2, ATM and PIM-1 kinases all known to be involved in the cascade of chemical signals that control cell division.
Evaluation of SF2523 in a 232 kinase panel screen showed that the compound selectively and potently inhibits key cancer kinase targets, including mTOR, DNA-PK
, PIM-1 and PI3K.
Our data provides evidence that Dbait specifically activates DNA-PK
but not ATM kinase activity, as the phosphorylation of H2AX is in a DNA-PK
SNS-595 acts selectively through DNA-PK
signaling in the S-phase of the cell cycle to kill proliferating cancer cells by inducing apoptosis, or programmed cell death.
According to the scientists, these new findings suggest that treating HIV-infected individuals with drugs that block early steps of viral replication-up to and including activation of DNA-PK
and integration-not only can prevent viral replication, but also may improve CD4+ T cell survival and immune function.
But the new treatment has been found to attack and destroy DNA-PK
6273743 U35835; DNA-dependent protein kinase U47077 (DNA-PK
catalytic subunit (DNA-PKCS) A7D 0.
Treatment with wortmannin (1 and 5 [micro]M), an inhibitor of DNA-PK
and ATM (Sarkaria et al.
SF1126 inhibits all four class I PI3K isoforms along with other cancer targets such as mTOR, DNA-PK
, PIM1, and PLK1.