VX-984 is an orally active, potent, selective and BBB-penetrated DNA-PK inhibitor. VX-984 efficiently inhibits NHEJ (non-homologous end joining) and increases DSBs (DNA double-strand breaks). VX-984 can be used for glioblastomas (GBM) and non-small cell lung cancer (NSCLC) research. VX-984 is a de novo deuterium[2].In Vitro:VX-984 (0-500 nM, 30 min) inhibits radiation-induced DNA-PKcs phosphorylation in U251 and NSC11 cells.
VX-984 (0-500 nM) enhances the radiosensitivity of U251 and NSC11 cells in a concentration-dependent manner.
VX-984 inhibits the repair of radiation-induced DNA double-strand breaks (DSBs).
VX-984 (0-1 μM) increases alternate pathways of DSB repair, including HR (homologous recombination) and mutagenic NHEJ (mNHEJ)[2].
Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs.
Potential advantages of deuterated compounds:
(1) Extend the half-life in vivo. Deuterated compounds may be able to prolong the pharmacokinetic characteristics of the compound, that is, prolong the half-life in vivo. This can improve compound safety, efficacy and tolerability, and increase ease of administration.
(2) Improve oral bioavailability. Deuterated compounds may reduce the degree of unwanted metabolism (first-pass metabolism) in the gut wall and liver, allowing a greater proportion of the unmetabolized drug to reach its target site of action. High bioavailability determines its activity at low doses and better tolerance.
(3) Improve metabolic characteristics. Deuterated compounds may reduce the formation of toxic or reactive metabolites and improve drug metabolism.
(4) Improve drug safety. Deuterated compounds may reduce or eliminate adverse side effects of pharmaceutical compounds and are safe.
(5) Preserve the therapeutic properties. Deuterated compounds are expected to retain similar biochemical potency and selectivity to hydrogen analogs in previous studies.
In Vivo:VX-984 (0-100 mg/kg, Oral gavage, daily) inhibits radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts.
VX-984 (0-50 mg/kg, Oral gavage, twice a day for 2 days) enhances the radiosensitivity of brain tumor xenografts.