Identification and characterization of TYK2 pseudokinase domain stabilizers that allosterically inhibit TYK2 signaling

Locke, Gregory; Muckelbauer, J.K.; Tokarski, John S.; Barbieri, Christopher M.; Belić, Stefan; Falk, Bradley T.; Tredup, Jeffrey; Wang, Ying-Kai

doi:10.1016/bs.mie.2022.03.051

Cited by 4 publications

(5 citation statements)

References 59 publications

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“…In conclusion, we describe the optimization of a series of potent and highly selective TYK2 JH2 inhibitors through the use of multiple orthogonal structural and computational methods, including virtual screening, FEP+ potency and solubility predictions, a computational RRCK predictive permeability model, and SBDD. A strategy to pursue pseudokinase domain (JH2) TYK2 inhibitors was crucial for achieving high selectivity over JAK1, JAK2, and JAK3 JH1 domains. ,, We used docking and SBDD to improve selectivity of the initial pyrazolopyrimidine series over PDE4D, and we were guided by FEP potency predictions and SBDD to identify a methoxycyclobutyl amide moiety that enhances binding to the hTYK2 JH2 domain to achieve a K D < 5 pM. Importantly, 30 is highly selective over the broader kinome, as well as against the JAK1 and JAK2 JH2 pseudokinase domains, with binding selectivity over a million-fold over these JH2 domains.…”

Section: Discussionmentioning

confidence: 99%

“…A strategy to pursue pseudokinase domain (JH2) TYK2 inhibitors was crucial for achieving high selectivity over JAK1, JAK2, and JAK3 JH1 domains. 19,53,54 We used docking and SBDD to improve selectivity of the initial pyrazolopyrimidine series over PDE4D, and we were guided by FEP potency predictions and SBDD to identify a methoxycyclobutyl amide moiety that enhances binding to the hTYK2 JH2 domain to achieve a K D < 5 pM. Importantly, 30 is highly selective over the broader kinome, as well as against the JAK1 and JAK2 JH2 pseudokinase domains, with binding selectivity over a million-fold over these JH2 domains.…”

Section: ■ Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

Leit¹,

Greenwood

Carriero³

et al. 2023

J. Med. Chem.

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TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

Leit¹,

Greenwood

Carriero³

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…From the kinase screening, it potently targets TYK2 JH2, JAK1 JH2, and IKKβ with >96% inhibition at 1 μM, 87 and has an IC 50 of 27 nM in a scintillation proximity assay against TYK2 JH2. 116 Notably, this ligand did not bind to the JH1 domain of any JAK.…”

Section: ■ the Jak Trans-activation State: A Tentative Keystonementioning

confidence: 94%

“…These assays identified 2 (Figure A) as a representative of an imidazothiazolopyridine (ITP) TYK2 JH2 ligand series. From the kinase screening, it potently targets TYK2 JH2, JAK1 JH2, and IKKβ with >96% inhibition at 1 μM, and has an IC 50 of 27 nM in a scintillation proximity assay against TYK2 JH2 . Notably, this ligand did not bind to the JH1 domain of any JAK.…”

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

Progress on the Pharmacological Targeting of Janus Pseudokinases

Henry

Jorgensen

2023

J. Med. Chem.

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The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets of many FDA-approved drugs, these drugs manifest adverse effects due in part to their inhibition of the requisite JAK kinase activity. However, the JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain. The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains. ■ SIGNIFICANCEThe JAK pseudokinase (JH2) domains present attractive targets for modulation of JAK-STAT pathways to circumvent adverse side effects of traditional Jakinibs. This has been demonstrated by the recent FDA approval of the TYK2 JH2 ligand deucravacitinib. Understanding the structure of these domains and the state of development of their ligands is important for future development of the JAK pseudokinases as therapeutic targets.

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“…Deucravacitinib is an allosteric inhibitor of TYK2 (175,176), a JAK family kinase responsible for mediating type I IFN response, including signaling by IFN-a (177) and IL-12/23 (178). Deucravacitinib is FDA approved and currently under consideration by the European Medicines Agency for the treatment of moderate to severe psoriasis (179).…”

Section: Jak Inhibitorsmentioning

confidence: 99%

Inhibition of T-cell activity in alopecia areata: recent developments and new directions

Passeron,

King,

Seneschal

et al. 2023

Front. Immunol.

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Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration–approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell–mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell–signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell–signaling pathways is also provided in this review.

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Identification and characterization of TYK2 pseudokinase domain stabilizers that allosterically inhibit TYK2 signaling

Cited by 4 publications

References 59 publications

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

Progress on the Pharmacological Targeting of Janus Pseudokinases

Inhibition of T-cell activity in alopecia areata: recent developments and new directions

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