DDEL-05. PHARMACOKINETICS AND CNS DISTRIBUTION OF A NOVEL ATM INHIBITOR, WSD0628, FOR THE TREATMENT OF BRAIN TUMORS

Abstract The treatment of brain tumors using chemo- and radio-sensitizers may be limited by a lack effective drug delivery. Radiation some cytotoxic therapies induce DNA damage, damage response (DDR) pathways modulate resistance to chemo-radiation therapy. Inhibiting DDR targeting ATM leads sensitization enhances cytotoxicity. purpose this study is determine the key pre-clinical pharmacokinetic parameters mechanisms that influence CNS delivery WSD0628, novel inhibitor. Pharmacokinetics distribution studies were conducted in FVB wild-type mice following intravenous (IV) oral (PO) dosing (5 mg/kg). Plasma, brain, spinal cord samples harvested after concentrations measured LC-MS/MS. free fraction WSD0628 was plasma, rapid equilibrium dialysis. Our results indicate has half-life 4.11 hrs high bioavailability (0.95). partition coefficient (AUCbrain/AUCplasma, i.e., Kp, brain) 0.05 0.11 IV PO dosing, respectively. plasma 2.01 ± 0.02 % it 1.22 0.40 %. unbound (Kpuu 0.03 0.06 differential binding tissues relatively low Kpuu, parameter describing penetrability. These data show highly potent inhibitor ATM, reached sufficient single dose 5 mg/kg engage over desired time frame elicit chemo-radiotherapy. shows promising potential further evaluations are underway if efflux transporters at BBB limit its distribution.