<scp>First‐in‐human</scp> study of deucravacitinib: A selective, potent, allosteric <scp>small‐molecule</scp> inhibitor of tyrosine kinase 2

Catlett, Ian M.; Aras, Urvi; Hansen, Lars; Liu, Yali; Bei, Di; Girgis, Ihab; Murthy, Bindu

doi:10.1111/cts.13435

Cited by 31 publications

(18 citation statements)

References 40 publications

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“…IL-12 stimulation of IFNγ production was inhibited by deucravacitinib ex vivo. 127,128 Deucravacitinib had modest effects on monocyte and granulocyte counts, 128 and did not induce anemia, thrombocytopenia, or neutropenia. 89 No significant cardiac effects, including QT prolongation, were observed in patients treated with deucravacitinib.…”

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

confidence: 99%

“…Deucravacitinib ( 3 ) is safe and well tolerated in humans and produced marginal adverse effects, the most significant of which were rashes, acne, and urticaria-like symptoms vs placebo that occurred at high doses. , IFNα-2a induced gene expression was blocked by deucravacitinib in humans, and deucravacitinib also blocked IFNα-2a-mediated reductions in lymphocytes. IL-12 stimulation of IFNγ production was inhibited by deucravacitinib ex vivo . , Deucravacitinib had modest effects on monocyte and granulocyte counts, and did not induce anemia, thrombocytopenia, or neutropenia .…”

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

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

confidence: 99%

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

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Progress on the Pharmacological Targeting of Janus Pseudokinases

Henry

Jorgensen

2023

J. Med. Chem.

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“…Psoriasis vulgaris is hereditarily not a homogenous malady, and unmistakable clinical sub-phenotypes of the malady appear to be subordinate to distinctive hereditary components [3,4]. Therefore, FDA in 2022 approved DEU (Figure 1) as a first-line oral and selective tyrosine kinase inhibitor [5,6]. DEU is a novel lingual small molecule that selectively impedes TYK2 by binding exclusively to the TYK2-regulated pseudo-kinase (JH2) domain (allosteric inhibition).…”

Section: Introductionmentioning

confidence: 99%

A Novel Bioanalytical HPLC-MS/MS Method for Deucravacitinib Determination in Human Plasma

Mahesh¹,

Haque²,

Salman³

et al. 2023

Preprint

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Plaque psoriasis is a common, long-lasting illness that affects the immune system and causes significant negative impacts on a patient's physical health, well-being, and ability to work effectively. Deucravacitinib (DEU) is the first oral medication used in the treatment of plaque psoriasis, a chronic skin condition that causes red, scaly patches on the skin. DEU is a type of medication called an oral Janus kinase (JAK) inhibitor, which works by blocking specific enzymes that play a role in the inflammation and immune response associated with psoriasis. Therefore, a quick, easy, novel, reliable, sensitive, and straightforward Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) approach was used to analyse DEU in plasma samples. The LC-MS/MS method for the determination of DEU in human plasma was based on using trimethoprim as an internal standard (IS). The separation of DEU and IS was carried out via liquid-liquid extraction (LLE). The isolated substances were then subjected to the chromatographic system using the ACE-C18 column (4.6x100 mm, 5 µm). The mobile phase employed consisted of methanol and a solution of 2 mM ammonium formate (80:20 v/v, respectively). The flow rate used was set at 0.9 mL min-1. The creative strategy was performed by running an ABSCIEX API 4000 mass spectrometer with an electron spray ionization source in Multiple Reaction Monitoring (MRM) modes. The ion transitions m/z 426.3  358.2 was used for DEU quantitation, while the ion transitions m/z 291.1  261.1 was used for trimethoprim quantitation. The accuracy, precision, linearity, recovery, and selectivity of DEU were deemed acceptable when validated for a concentration range between 0.500 to 601.050 ng/mL, utilizing a weighting factor of 1/x2.

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“…[5][6][7] In a pharmacokinetic (PK) study of healthy adults, deucravacitinib (BMS-986165) was rapidly absorbed and had an apparent elimination terminal half-life (t 1/2 ) of 7.9-15.0 hours following a single dose and a mean effective t 1/2 range of 7.5-13.1 hours after multiple dosing. 8 Following a single dose of deucravacitinib up to 10 mg, the maximum plasma concentration (C max ) exhibited greater-than-proportional increases with ascending doses. 8 Following multiple doses, the PK profile was similar to that of single dosing, with proportionality observed at doses ≥4 mg twice daily.…”

mentioning

confidence: 99%

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans

Chimalakonda,

Li,

Marchisin

et al. 2023

Clinical Pharm in Drug Dev

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Abstractitinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune‐mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open‐label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12‐mg tablet and an intravenous microdose infusion of 0.1‐mg carbon‐13 and nitrogen‐15–labeled deucravacitinib ([13C2, 15N3] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3‐ and 12‐mg dose levels in 20 subjects. The absolute oral availability of deucravacitinib in the tablet formulation was near complete at approximately 99%. The total clearance (254 mL/min) was low relative to hepatic blood flow, and volume of distribution (∼140 L) was greater than total body water, indicating extravascular distribution. Deucravacitinib systemic exposure (maximum plasma concentration, area under the plasma drug concentration curve from time zero to the time of the last quantifiable nonzero concentration, and area under the plasma drug concentration–time curve from time zero extrapolated to infinity) after administration of the tablet formulation were similar to the capsule at the tested 3‐ and 12‐mg doses. In both studies, deucravacitinib was safe with no clinically relevant changes in laboratory values, electrocardiogram parameters, or vital signs.

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First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2

Cited by 31 publications

References 40 publications

Progress on the Pharmacological Targeting of Janus Pseudokinases

Progress on the Pharmacological Targeting of Janus Pseudokinases

A Novel Bioanalytical HPLC-MS/MS Method for Deucravacitinib Determination in Human Plasma

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans

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