A novel Bruton's tyrosine kinase inhibitor JDB175 shows potent efficacy to suppress central nervous system lymphoma.

Abstract

Patients with central nervous system (CNS) lymphoma face limited treatment options and poor treatment outcomes, emphasizing the urgent need for effective therapeutic strategies. One limiting factor contributing to the suboptimal efficacy is the inadequate penetration of most treatment drugs across the blood-brain barrier (BBB). Recent insights into the pathophysiology of CNS lymphoma have identified the Bruton's tyrosine kinase (BTK) signaling pathway as a potential target. Some clinical trials have shown impressive responses to BTK inhibitors in CNS lymphoma. However, currently approved BTK inhibitors have low BBB penetration rates, limiting their efficacy. In this study, we discovered that JDB175, a novel and highly selective BTK inhibitor, exhibits excellent BBB penetration capabilities and demonstrates favorable activity in a mouse model of CNS lymphoma while showing no significant signs of toxicity. JDB175 effectively inhibits the BTK signaling pathway in human lymphoma cells, suppressing their proliferation, inducing cell cycle arrest, and promoting apoptosis. The significance of this study lies in addressing the critical unmet medical need for effective treatments for CNS lymphoma. This finding indicates a promising avenue for improved treatments in CNS lymphoma, potentially opening doors for further clinical investigation and therapeutic advancements.