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.

Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

Sodium is considered the mineral most limiting to growth and reproduction of mammalian herbivores worldwide. Notwithstanding the large database on physiological adaptations to low sodium intake, information on maintenance sodium requirements and sodium dynamics of mammals is depauperate. We measured sodium intake and output in adult, nonreproductive white-tailed deer (n = 15) over four seasons to estimate daily requirements for sodium on a seasonal and an annual basis. Dietary sodium content was based on best available predictions of sodium requirements. With regression techniques, we estimated metabolic fecal excretion and endogenous urinary losses of sodium. Average daily sodium requirement, defined as the minimum sodium intake at which intake equaled excretion, was estimated to be 3.27 mg kg-1 body mass d-1. Seasonal estimates did not vary. We propose that sodium requirements for maintenance in mammalian herbivores scale to body mass at an exponent that is similar to that for metabolic rate and forage intake (0.71-0.75). Development of an allometric relationship between sodium need and body mass would permit stronger inference regarding the role of sodium in population regulation, foraging decisions, or distribution and movements of mammalian herbivores.

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