<br/>BIIB091 is a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation. In contrast to most BTK inhibitors currently in the clinic, Biogen’s proprietary chemical matter binds in the “H3” pocket, which is necessary for obtaining exquisite kinome selectivity and translating to improved safety/tolerability in preclinical chronic toxicological studies. In addition, binding in the “H3” pocket enabled BIIB091 to sequester Tyr-551, an important phosphorylation site on BTK into an inactive conformation with excellent affinity and was demonstrated to block the binding of covalent probes to the BTK protein in whole blood assay under both stimulated and unstimulated conditions.  Multiple covalent and non-covalent BTK inhibitors have been disclosed to be advancing through clinical trials in the past 12 months.  This presentation of the preclinical data for BIIB-091 will add to the understanding of the therapeutic potential for BTK inhibitors by describing the safety profile and clinical target engagement possible with a highly selective, reversible inhibitor.<br/>

Discovery of BIIB091, a reversible selective potent BTK inhibitor for the treatment of Multiple Sclerosis

ACS Fall 2020 Virtual Meeting

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