PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

Coffey, Greg; Rani, Aradhana; Betz, Andreas; Pak, Yvonne; Haberstock-Debić, Helena; Pandey, Anjali; Stanley, Hollenbach; Gretler, Daniel D.; Mant, Tim; Jurčević, Stipo; Sinha, Uma

doi:10.1002/jcph.794

Cited by 15 publications

(11 citation statements)

References 46 publications

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“…Given the central role for the tyrosine kinase Syk in FcεRI-mediated signaling, we evaluated whether pharmacologic inhibition of Syk using the potent and selective small molecule inhibitor PRT062607 (Coffey et al, 2017; Spurgeon et al, 2013) could ameliorate development of murine osteoarthritis. Treatment of mice with PRT062607 for 12 weeks following DMM markedly reduced the development and/or severity of osteoarthritis compared to vehicle-treated mice (Figure 5e).…”

Section: Resultsmentioning

confidence: 99%

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

Wang

Lepus

Raghu

et al. 2019

eLife

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Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

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Section: Resultsmentioning

confidence: 99%

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

Wang

Lepus

Raghu

et al. 2019

eLife

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“…Blood cells were collected and evaluated by flow cytometry per instructions (BÜHLMANN Laboratories AG, Switzerland). [9][10][11] Those cells were treated ex vivo with an antibody that cross-links the Fcε receptor 1 (FcεRI) and the high-affinity immunoglobulin E receptor on basophils. Anti-FcεRI induced signaling through a pathway requiring BTK activity, resulting in the upregulation of CD63 expression at the cell surface.…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

“…The basophil activation test (BAT) is a flow cytometry‐based assay that directly measured CCR3‐positive basophil activation and degranulation based on CD63 surface expression. Blood cells were collected and evaluated by flow cytometry per instructions (BÜHLMANN Laboratories AG, Switzerland) 9–11 . Those cells were treated ex vivo with an antibody that cross‐links the Fcε receptor 1 (FcεRI) and the high‐affinity immunoglobulin E receptor on basophils.…”

Section: Methodsmentioning

confidence: 99%

A Phase I, Randomized, Double‐Blind, Placebo‐Controlled, Single‐Dose and Multiple‐Rising‐Dose Study of the BTK Inhibitor TAK‐020 in Healthy Subjects

Esfandiari

Chen

Smithson

et al. 2021

Clinical Translational Sci

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Bruton’s tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK‐020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK‐020 in healthy subjects. Each cohort of the single‐rising dose (n = 72; 9 cohorts) and the multiple‐rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK‐020‐treated and two placebo‐treated, subjects aged 18–55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)‐mediated activation of basophils. Overall, treatment‐emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK‐020 was rapidly absorbed (median time to maximum plasma concentration (Tmax) 45–60 minutes) with a half‐life of ~ 3–9 hours at doses ≥ 2.5 mg. TAK‐020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI‐mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24–72 hours postdose and the duration generally increased with dose. TAK‐020 was generally well‐tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.

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“…The partially selective Syk inhibitor fostamatinib showed clinical benefit in rheumatoid arthritis patients (63) and has been also investigated in other autoimmune and allergic diseases but considerable adverse events possibly due to its poor selectivity profile led to the suspension of further investigations in RA. New and more specific Syk inhibitors have been developed in the past few years (summarized in Table 2) that show promising results in this regard according to in vitro results, animal models of autoimmune arthritis and phase I clinical trials (41, 43, 44, 64).…”

Section: Signal Transduction By Tyrosine Kinasesmentioning

confidence: 99%

Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

2019

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Tyrosine kinases relay signals from diverse leukocyte antigen receptors, innate immune receptors, and cytokine receptors, and therefore mediate the recruitment and activation of various leukocyte populations. Non-receptor tyrosine kinases of the Jak, Src, Syk, and Btk families play major roles in various immune-mediated disorders, and small-molecule tyrosine kinase inhibitors are emerging novel therapeutics in a number of those diseases. Autoimmune and inflammatory skin diseases represent a broad spectrum of immune-mediated diseases. Genetic and pharmacological studies in humans and mice support the role of tyrosine kinases in several inflammatory skin diseases. Atopic dermatitis and psoriasis are characterized by an inflammatory microenvironment which activates cytokine receptors coupled to the Jak-Stat signaling pathway. Jak kinases are also implicated in alopecia areata and vitiligo, skin disorders mediated by cytotoxic T lymphocytes. Genetic studies indicate a critical role for Src-family kinases and Syk in animal models of autoantibody-mediated blistering skin diseases. Here, we review the various tyrosine kinase signaling pathways and their role in various autoimmune and inflammatory skin diseases. Special emphasis will be placed on identification of potential therapeutic targets, as well as on ongoing preclinical and clinical studies for the treatment of inflammatory skin diseases by small-molecule tyrosine kinase inhibitors.

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PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

Cited by 15 publications

References 46 publications

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis

A Phase I, Randomized, Double‐Blind, Placebo‐Controlled, Single‐Dose and Multiple‐Rising‐Dose Study of the BTK Inhibitor TAK‐020 in Healthy Subjects

Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

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