Bruton’s
tyrosine kinase (BTK), a non-receptor tyrosine
kinase, is a member of the Tec family of kinases and is essential
for B cell receptor (BCR) mediated signaling. BTK also plays a critical
role in the downstream signaling pathways for the Fcγ receptor
in monocytes, the Fcε receptor in granulocytes, and the RANK
receptor in osteoclasts. As a result, pharmacological inhibition of
BTK is anticipated to provide an effective strategy for the clinical
treatment of autoimmune diseases such as rheumatoid arthritis and
lupus. This article will outline the evolution of our strategy to
identify a covalent, irreversible inhibitor of BTK that has the intrinsic
potency, selectivity, and pharmacokinetic properties necessary to
provide a rapid rate of inactivation systemically following a very
low dose. With excellent in vivo efficacy and a very desirable tolerability
profile, 5a (branebrutinib, BMS-986195) has advanced
into clinical studies.
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
We describe an extension to the matched molecular pairs approach that merges pairwise activity differences with three-dimensional contextual information derived from X-ray crystal structures and binding pose predictions. The incorporation of 3D binding poses allows the direct comparison of structural changes to diverse chemotypes in particular binding pockets, facilitating the transfer of SAR from one series to another. Integrating matched pair data with the receptor structure can also highlight activity patterns within the binding site--for example, "hot spot" regions can be visualized where changes in the ligand structure are more likely to impact activity. The method is illustrated using P38α structural and activity data to generate novel hybrid ligands, identify SAR transfer networks, and annotate the receptor binding site.
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