TY - JOUR T1 - Brain distribution of berzosertib: an ATR inhibitor for the treatment of glioblastoma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000845 SP - JPET-AR-2021-000845 AU - Surabhi Talele AU - Wenjuan Zhang AU - Danielle M. Burgenske AU - Minjee Kim AU - Afroz S Mohammad AU - Sonja Dragojevic AU - Shiv K. Gupta AU - Ranjit S. Bindra AU - Jann N. Sarkaria AU - William F. Elmquist Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/09/23/jpet.121.000845.abstract N2 - The effective treatment of brain tumors is a considerable challenge in part due to the presence of the blood-brain barrier (BBB) that limits drug delivery. Glioblastoma (GBM) is an aggressive and infiltrative primary brain tumor with an extremely poor prognosis following standard of care therapy with surgery, radiation therapy (RT), and chemotherapy. DNA damage response (DDR) pathways play a critical role in DNA repair in cancer cells, and inhibition of these pathways can potentially augment RT and chemotherapy tumor cell toxicity. The Ataxia Telangiectasia and Rad3-Related (ATR) kinase is a key regulator of the DDR network and is potently and selectively inhibited by the ATR inhibitor, berzosertib. While in vitro studies demonstrate a synergistic effect of berzosertib in combination with temozolomide (TMZ), in vivo efficacy studies have yet to recapitulate this observation using intracranial tumor models. In the current study, we demonstrate that delivery of berzosertib to the brain is restricted by efflux at the BBB. Berzosertib has a high binding affinity to brain tissue compared to plasma, thereby leading to low free drug concentrations in the brain. Berzosertib distribution is heterogenous within the tumor, where concentrations are substantially lower in normal brain and invasive tumor rim (where the BBB is intact) when compared to the tumor core (where the BBB is leaky). These results demonstrate that high tissue binding and limited and heterogenous brain distribution of berzosertib may be important factors that influence the efficacy of berzosertib therapy in GBM. Significance Statement This study examined the brain delivery and efficacy of the potent ATR inhibitor - berzosertib, in PDX models of GBM. Berzosertib is actively effluxed at the BBB and is highly bound to brain tissue leading to low free drug concentrations in the brain. Berzosertib is heterogeneously distributed into different regions of the brain and tumor and was not efficacious in vivo when combined with TMZ. These factors inform the future clinical utility of berzosertib for GBM. ER -