Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune Diseases

Chang, Yu Ming; Xu, Shilin; Ding, Ke

doi:10.1021/acs.jmedchem.9b01612

Cited by 18 publications

(25 citation statements)

References 5 publications

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“…[46b] Currently, BMS-986165, as the first selective allosteric TYK2 inhibitor, is undergoing phase III clinical trial for psoriasis. [7] 4. Targeting the Extracellular Domain of Kinase (Type VII)…”

Section: Type IV Allosteric Inhibitorsmentioning

confidence: 99%

“…[6] For example, the first pseudokinase-directed clinical candidate, BMS-986165, a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), has recently been described. [7] Inhibitors that exploit binding sites in the pseudokinase domain to allosterically regulate the activity of a kinase are defined as type VI binders (Figure 1 C). In addition, there are some reported small-molecule inhibitors that target the extracellular domain (ECD) of a receptor tyrosine kinase (RTK) to allosterically inhibit substrate binding or induce conformational changes with a pathway-biased allosteric mechanism.…”

Section: Introductionmentioning

confidence: 99%

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New Promise and Opportunities for Allosteric Kinase Inhibitors

2020

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Drugs that function through allosteric inhibition of kinase signaling represent a promising approach for the targeted discovery of therapeutics. The majority of developed allosteric kinase inhibitors are characterized as type III and IV inhibitors that show good kinome selectivity but generally lack the subtype selectivity of same kinase family. Recently allosteric inhibitors have been developed that bind outside the catalytic kinase domain with high selectivity for specific kinase subtypes. Allosteric inhibitors that bind to the pseudokinase domain of pseudokinase or the extracellular domain of receptor tyrosine kinases are reviewed. We also review recent developments in the field of allosteric kinase inhibitors including examples of proteolysis targeting chimeras, and highlight the unique binding modes for each type of inhibitors and address future opportunities in this area.

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Section: Type IV Allosteric Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Promise and Opportunities for Allosteric Kinase Inhibitors

2020

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“…Deucravacitinib (formerly known as BMS-986165) is a novel, oral, selective TYK2 inhibitor with a mechanism of action distinct from that of JAK1-3 inhibitors. 24 , 45 , 50 , 51 Deucravacitinib inhibits TYK2 by binding to the regulatory (JH2 pseudokinase) domain rather than directly to the active site in the catalytic domain as JAK1-3 inhibitors do ( Fig. 4 ).…”

Section: Deucravacitinibmentioning

confidence: 99%

Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise

Danese

Peyrin–Biroulet

2021

Inflammatory Bowel Diseases

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Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

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“…The most common infective events reported were pharyngitis and upper respiratory tract infections, but they were mild-to-moderate and did not lead to treatment discontinuation. 18 The different clinical subtypes of psoriasis could be related to different cytokines involved in the pathogenesis. For instance, recessive mutations in the antagonist of the IL-36R, belonging to the IL-1 proinflammatory cytokine family, have been linked to GPP.…”

Section: Discussionmentioning

confidence: 99%

“…Selective TYK2 inhibitors are of great interest for increasing the target specificity and reducing AEs observed with other types of JAKsI. 10,18 Pembrocitinib (PF-06700841) is an oral, dual selective TYK2/JAK1 inhibitor, targeting multiple cytokines involved in the signaling (IFN, IL-6, IL-12, IL-21, IL-22, and IL-23), tested to treat patients with moderate-to-severe plaque psoriasis. From oral formulation, a topical cream 0.1% has been produced and tested in a Phase II trial (Table 1; Figure 2; Table S2).…”

Section: Janus Kinases Inhibitorsmentioning

confidence: 99%

Experimental Pharmacological Management of Psoriasis

Campione¹,

Cosio²,

Prete³

et al. 2021

JEP

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Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words "psoriasis" and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies -especially systemic ones and those using small molecules -and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/ tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.

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Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune Diseases

Cited by 18 publications

References 5 publications

New Promise and Opportunities for Allosteric Kinase Inhibitors

New Promise and Opportunities for Allosteric Kinase Inhibitors

Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise

Experimental Pharmacological Management of Psoriasis

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