Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis

Multiple Sclerosis is a chronic autoimmune
neurodegenerative disorder
of the central nervous system (CNS) that is characterized by inflammation,
demyelination, and axonal injury leading to permeant disability. In
the early stage of MS, inflammation is the primary driver of the disease
progression. There remains an unmet need to develop high efficacy
therapies with superior safety profiles to prevent the inflammation
processes leading to disability. Herein, we describe the discovery
of BIIB091, a structurally distinct orthosteric ATP competitive, reversible
inhibitor that binds the BTK protein in a DFG-in confirmation designed
to sequester Tyr-551, an important phosphorylation site on BTK, into
an inactive conformation with excellent affinity. Preclinical studies
demonstrated BIB091 to be a high potency molecule with good drug-like
properties and a safety/tolerability profile suitable for clinical
development as a highly selective, reversible BTKi for treating autoimmune
diseases such as MS.