No abstract

Skin fibroblasts from a patient w gous familial hypercholesterolemia (HFH) were with normal skin fibroblasts with regard to bindii ization, and degradation of iodinated human low poprotein (LDL). Like other cell lines from HF the mutant cells showed no suppression of sterol s LDL. Surface binding, measured at O0 to elimir preciable internalization that was shown to occur on the average slightly less for HFH cells than X at low LDL concentrations but comparable or e at high LDL concentrations (>60 ,gg of LDL prot A major defect observed was in the rate of intern LDL at 370, which was only 1-10% of that in n LDL degradation was also markedly reduced bu same extent. Thus, a larger fraction of the LDL t peared to be degraded by the mutant cells. The n defect observed, then, was not in surface binding in rate of LDL internalization. While this migi dary to a defect in specific binding sites of LDL tude of the observed differences in binding at Il ture seems too small to account for the huge dil internalization (13-to 115-fold).

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.

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.