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

Leit, Silvana; Greenwood, Jeremy R.; Carriero, Samantha; Mondal, Sayan; Abel, Robert; Ashwell, Mark A.; Blanchette, Heather S.; Boyles, Nicholas A.; Cartwright, Mark E.; Collis, Alan; Feng, Shulu; Ghanakota, Phani; Harriman, Geraldine; Hosagrahara, Vinayak; Kaila, Neelu; Kapeller, Rosanna; Rafi, Salma B.; Romero, Donna L.; Tarantino, Patrizia; Timaniya, Jignesh B.; Toms, A.V.; Wester, Ronald T.; Westlin, William; Bhaskar, Suryanarayanan; Miao, Wenyan; Tummino, Peter J.; McElwee, Joshua; Edmondson, Scott D.; Masse, C. E.

doi:10.1021/acs.jmedchem.3c00600

Cited by 21 publications

(5 citation statements)

References 55 publications

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“…Fragment optimization appears well placed to make use of physics-based computational methods, such as relative and absolute free energy perturbation (FEP), particularly when allied with experimentally derived structural information. These techniques have been used successfully in later-stage hit-to-lead and lead optimization programs; , however, challenges persist with fragments. Binding mode preservation for fragment-sized compounds during molecular dynamic simulations is not guaranteed, and the limited number of known perturbations for novel fragment hits makes predicting the affinity of new designs challenging.…”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015−2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911). ■ SIGNIFICANCEFragment-based methodologies have become firmly established within the drug discovery community, and with the recent FDA approval of capivasertib, there are now seven fragment-derived drugs approved for clinical use. This Perspective provides case studies of successful fragment-tolead examples for 2022 and discusses various trends, including target classes, screening methods, and physicochemical properties, compared with previous years.

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Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Woodhead,

Erlanson,

de Esch

et al. 2024

J. Med. Chem.

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“…Of note, potency of all compounds decreased in whole blood assays compared with PBMC. This is likely due to the absence of serum in the PBMC assays that delivers free fraction activity, while in whole blood, part of the molecules are trapped by plasma protein as frequently documented. , …”

Section: Resultsmentioning

confidence: 99%

“…The absence of a dose–response relationship is likely due to the involvement of other pathways not impacted by TYK2 inhibition, and to the fact that mass balance studies in mice showed that compound 9 was highly concentrated in the skin (data not shown), suggesting that despite unfavorable PK, it displayed a strong effect in this psoriasis-like model. In addition, it is noteworthy that Leit et al (2023) observed the same partial effects with the TYK2 inhibitor TAK-279, while this compound is more potent than compound 9 and displayed more favorable PK. Other compounds from the same series also gave a partial effect, strongly suggesting that in this model TYK2 inhibitors may not be able to fully counteract all the effects of IL-23.…”

Section: Resultsmentioning

confidence: 99%

Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases

Mammoliti,

Martina,

Claes

et al. 2024

J. Med. Chem.

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Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).

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“…There are currently no available data on BMS-986322 in patients with psoriasis. TAK-279 (formerly, NDI-034858) is an allosteric TYK2 inhibitor developed by Takeda Therapeutics [73][74][75][76]. In preclinical trials, TAK-279 was 13.0 × 10 4 times more selective for the TYK2-JH2 domain than deucravacitinib, owing to a single amino acid difference in its allosteric binding pocket that prevents binding to JAK1 [74,75].…”

Section: Janus Kinase Inhibitorsmentioning

confidence: 99%

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

Drakos,

Torres,

Vender

2024

Pharmaceutics

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The introduction of biologic agents for the treatment of psoriasis has revolutionized the current treatment landscape, targeting cytokines in the interleukin (IL)-23/IL-17 pathway and demonstrating strong efficacy and safety profiles in clinical trials. These agents however are costly, are associated with a risk of immunogenicity, and require administration by intravenous or subcutaneous injection, limiting their use among patients. Oral therapies, specifically small molecule and microbiome therapeutics, have the potential to be more convenient and cost-effective agents for patients and have been a focus of development in recent years, with few targeted oral medications available for the disease. In this manuscript, we review pipeline oral therapies for psoriasis identified through a search of ClinicalTrials.gov (30 June 2022–1 October 2023). Available preclinical and clinical trial data on each therapeutic agent are discussed. Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients.

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

Cited by 21 publications

References 55 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Fragment-to-Lead Medicinal Chemistry Publications in 2022

Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

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