Abstract
Abstract BTK is a member of the TEC family of kinases and is a critical component of B cell receptor (BCR) signaling, promoting B cell maturation, survival and proliferation. BCR signaling is requisite in all B cell-mediated malignancies where clinical trials with BTK inhibitors have proven efficacious. X-Rx utilized its drug discovery platform and knowhow to advance multiple novel series of BTK inhibitors. X-022 was then identified as a next generation, oral small molecule BTK inhibitor. X-022 irreversibly inhibits BTK with an IC50 of 2.3 nM. In primary human B cell and HWB assays, X-022 inhibited B cell activity with IC50 values of 49 and 93 nM, respectively. X-022 showed superior selectivity against a panel of 456 kinases, only inhibiting at >90% BTK at a concentration of 1000 nM. Oral bioavailability of >20% is observed in mice, rats and dogs. In a mouse PK/PD model, X-022 showed a dose dependent decrease in B cell activation measured over an 8 hour time interval with >98% inhibition observed at 10 mg/kg po. In an established model of collagen induced arthritis in mice, X-022 caused a dose dependent decrease in disease severity consistent with mechanism of action. No safety issues were identified in a pilot study in rodents at doses up to 300 mg/kg po. X-022 is a promising next generation irreversible oral BTK inhibitor for the treatment of B cell malignancies and chronic autoimmune diseases. In addition, the high degree of selectivity combined with favorable molecular properties make X-022 an excellent candidate for co-formulation with other targeted therapeutics. Citation Format: Mark J. Mulvihill, Xiangyang Chen, JP Shaw, Richard Liu, Haihong Ni, Lee Babiss, Louis Renzetti. Suppression of Bruton tyrosine kinase with X-022, a highly selective next-generation irreversible inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-234. doi:10.1158/1538-7445.AM2014-LB-234
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