P1247: GB5121 IS A NOVEL, IRREVERSIBLE, COVALENT BTK INHIBITOR WITH HIGH SELECTIVITY AND CNS-PENETRANCE FOR TREATMENT OF CNS MALIGNANCIES

Abstract

Background: 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) penetration. GB5121 is an orally available, selective, irreversible, covalent small molecule BTK inhibitor that was designed to address these limitations. Aims: To profile GB5121 for selectivity, potency, inactivation kinetics and CNS penetrance in comparison to ibrutinib. Methods: Selectivity of GB5121 and ibrutinib were assessed in kinome scans against 349 kinases at 1 µM compound concentration with 1mM ATP. Irreversible and covalent nature of GB5121 was evaluated using enzymatic assays compared to analogs that lacked an active covalent warhead. Both biochemical and cell-based assays were employed for evaluation of potency and inactivation kinetics of GB5121. For assessment of BTK target occupancy within the CNS, naïve mice with an intact blood brain barrier were dosed with either GB5121 or ibrutinib followed by perfusion, brain dissection and processing into lysates that were analyzed for unoccupied BTK in a probe-based ELISA assay. The pharmacokinetic profile of GB5121 was assessed in multiple species for both intravenous (IV) and oral routes of dosing. Results: In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating >50% inhibition at 1 µM; additionally, GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. Importantly, GB5121 demonstrated rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissues, a critical parameter for covalent irreversible inhibitors. When compared with ibrutinib, GB5121 showed superior CNS target occupancy in the brain of mice receiving three daily oral doses and demonstrated significantly higher brain to plasma ratio. 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. Summary/Conclusion: The unique profile of GB5121 provides differentiation from both FDA-approved BTK inhibitors and 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. This research has been previously presented at the AACR Annual Meeting 2022.