The Janus kinase (JAK) family of non-receptor tyrosine kinases that include JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase-2) are known to be critical mediators of pro-inflammatory cytokine signaling. Orally-active small molecule inhibitors that target these isoforms with varying levels of selectivity have shown to be effective treatments for patients suffering from serious autoimmune diseases where cytokines are involved in disease pathogenesis. Deucravacitinib is a first-in-class TYK2 inhibitor that binds to the unique pseudokinase domain of TYK2 and functions through a unique highly selective allosteric mechanism in large part due to a deuterated methyl (CD<sub>3</sub>) amide group as a key pharmacophore. This presentation will highlight the medicinal chemistry efforts and the de novo design strategy that led to the incorporation of deuterium in the discovery of deucravacitinib.

Discovery of deucravacitinib: A first-in-class, allosteric TYK2 inhibitor for the treatment of autoimmune diseases

ACS Spring 2022

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