JAK Family Inhibitors for Autoimmune Diseases

Abstract

The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.

Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors

“…Five points should be noted: (i) a hydrogen bond donor−acceptor−donor motif within the hinge region; (ii) the d 3 -N-methyl amide occupying an uncommon "alanine pocket" necessary for selectivity; (ii) deuterium incorporated during the optimization process to address the potential metabolic liability; (iii) the cyclopropyl carboxamide replacement leading to reduced hERG inhibition; (iv) a C2′ methoxy group affording hydrogen bond and hydrophobic interactions as well as conformational control; and (v) C3′ heteroaromatic rings providing hydrogen bond interactions and modulating DMPK properties. 143,148 4. was still modification space below the P loop (around the triazole ring) to further improve potency. 149,150 Replacing the triazole group with different amides led to various TYK2 JH2 ligands.…”

“…Collectively, the SARs of N -methyl nicotinamide and pyridazine-3-carboxamide TYK2 JH2 ligands are summarized and shown in Figure . Five points should be noted: (i) a hydrogen bond donor–acceptor–donor motif within the hinge region; (ii) the d 3 - N -methyl amide occupying an uncommon “alanine pocket” necessary for selectivity; (ii) deuterium incorporated during the optimization process to address the potential metabolic liability; (iii) the cyclopropyl carboxamide replacement leading to reduced hERG inhibition; (iv) a C2′ methoxy group affording hydrogen bond and hydrophobic interactions as well as conformational control; and (v) C3′ heteroaromatic rings providing hydrogen bond interactions and modulating DMPK properties. , …”