Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165

Small
molecule JAK inhibitors have emerged as a major therapeutic
advancement in treating autoimmune diseases. The discovery of isoform
selective JAK inhibitors that traditionally target the catalytically
active site of this kinase family has been a formidable challenge.
Our strategy to achieve high selectivity for TYK2 relies on targeting
the TYK2 pseudokinase (JH2) domain. Herein we report the late stage
optimization efforts including a structure-guided design and water
displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor
of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal
profiling liabilities and is efficacious in several murine models
of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and
has been advanced as the first pseudokinase-directed therapeutic in
clinical development as an oral treatment for autoimmune diseases.