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

Abstract

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