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Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) penetrance in instances of CNS disease. GB5121 is an orally available, selective, irreversible small molecule BTK inhibitor. GB5121 was selected based on its potency, specificity, and high brain penetrance in preclinical models. We evaluated its pharmacodynamic properties using both cell-free enzymatic and cell-based functional assays, showing covalent BTK inactivation with a potency in the nM range. GB5121 furthermore demonstrated rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissue, a critical parameter for covalent irreversible inhibitors. In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating >50% inhibition at 1 µM; GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. When compared with other BTK inhibitors, GB5121 showed superior CNS target occupancy using a probe-based ELISA measuring free BTK in the brain of mice receiving 3 daily oral doses of 10 mg/kg. GB5121 also demonstrated significantly higher brain to plasma ratio in mice with an intact blood brain barrier. Specifically, GB5121 showed ~2-fold higher brain concentrations with lower plasma levels than ibrutinib. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Together, these features differentiate GB5121 from both FDA-approved BTK inhibitors as well as those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including in CNS lymphoma. Citation Format: Isharat Yusuf, Sunil Sahdeo, Taylor Ismaili, Zachary Naiman, David Guimond, Theodore Schiff, Bryan Clemons, Krystal Herman, Bryanna Paulson, Kay Hou, Kristen Taylor Meadows, Michael Kennedy, Mark Rose, Laura Carter. GB5121 is a novel highly potent and selective CNS-penetrant BTK inhibitor for CNS malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3330. |
