Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on - and off - target inhibition

Liclican, Albert; Serafini, Loredana; Xing, Weimei; Czerwieniec, Gregg; Steiner, Bart; Wang, Ting; Brendza, Katherine M.; Lutz, Justin D.; Keegan, Kathleen; Ray, Adrian S.; Schultz, Brian E.; Sakowicz, Roman; Feng, Joy Y.

doi:10.1016/j.bbagen.2020.129531

Cited by 66 publications

(95 citation statements)

References 29 publications

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“…[21][22][23][24][25] This is likely because ibrutinib has some off-target effects, including inhibition of other tyrosine kinases such as EGFR, tyrosine kinase expressed in hepatocellular carcinoma, the phosphoinositide 3-kinase/AKT cardio protective pathway, and interleukin-2-inducible T-cell kinase. 26 A systematic review and meta-analysis of ibrutinib treatment for patients with CLL demonstrated an increased risk of these toxicities, which led to the discontinuation of ibrutinib. 22,23 Thus, the development of an effective treatment for WM with a reduced incidence of these toxicities would contribute to a longer response duration.…”

Section: Introductionmentioning

confidence: 99%

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

et al. 2020

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Tirabrutinib is a second‐generation Bruton’s tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment‐naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström’s macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression‐free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow‐up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. Although the follow‐up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI‐173646).

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Section: Introductionmentioning

confidence: 99%

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

et al. 2020

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“…No major bleeding was reported in this clinical trial but still a significant percentage of low grade bleeding was noted 19 . Tirabrutinib (ONO‐4059/GS‐4059), another covalent and selective oral inhibitor of Btk, is under evaluation 20–23 . A clinical trial enrolling 28 patients has reported its efficacy.…”

Section: Introductionmentioning

confidence: 84%

“…19 Tirabrutinib (ONO-4059/GS-4059), another covalent and selective oral inhibitor of Btk, is under evaluation. [20][21][22][23] A clinical trial enrolling 28 patients has reported its efficacy. Low-grade bleeding events (35.7% of patients had bruising and 25% hematoma) were also observed in patients receiving tirabrutinib.…”

Section: Introductionmentioning

confidence: 99%

Effects of novel Btk and Syk inhibitors on platelet functions alone and in combination in vitro and in vivo

Series

Ribes

Garcia

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Inhibitors of tyrosine kinases downstream of the B-cell receptor, such as Bruton's tyrosine kinase (Btk) or Spleen tyrosine kinase (Syk), used alone or in combination are new therapeutic options in the treatment of B-cell malignancies. A challenge in the development of second-generation Btk inhibitors is to limit their side effects such as the increased bleeding risk. Considering the pivotal role of Syk in immunoreceptor tyrosine-based activation motif mediated platelet signaling, the impact of inhibiting this kinase on platelet functions is also worth analyzing. Objectives: We investigated the effect of a novel Btk inhibitor, tirabrutinib, and a Syk inhibitor, entospletinib, alone and in combination on platelet signaling and functions in vitro and ex vivo. Methods: Platelet aggregation, secretion, and signaling responses as well as thrombus growth under flow were analyzed in the presence of the inhibitors alone or in combination in vitro, at clinically relevant doses, and ex vivo in patients treated with these inhibitors in the context of a phase I trial. Results: Although tirabrutinib alone had modest effects on platelet activation in vitro and ex vivo, entospletinib alone efficiently inhibited washed platelet aggregation in response to collagen. However, entospletinib weakly affected platelet activation in platelet-rich plasma, in whole blood and ex vivo. Importantly, the combination of tirabrutinib and entospletinib induced a significant decrease in platelet response to collagen in vitro and ex vivo correlating with mild bleedings reported in some of the treated patients. Conclusion: These new results should contribute to improve the safety of these targeted therapies.

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“…Safety and efficacy of evobrutinib in subjects with RA with stable MTX therapy or with inadequate response to MTX was evaluated in a phase IIa-b, randomized and double-blind studies (NCT02784106, NCT03233230). Tirabrutinib (GS-4059/ONO-4059) is a selective oral BTK inhibitor with clinical activity against many relapsed/refractory B-cell malignancies [ 80 ]. Safety and pharmacokinetics of GS-4059 in healthy volunteers and RA patients were evaluated in phase I placebo-controlled randomized study (NCT02626026), but no results have been posted.…”

Section: Tsdmards Based On Jaks/mapks/nf-κb/syk-btk-targeted Theramentioning

confidence: 99%

Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Massalska

Maśliński

Ciechomska

2020

Cells

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The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

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Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on - and off - target inhibition

Cited by 66 publications

References 29 publications

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

Effects of novel Btk and Syk inhibitors on platelet functions alone and in combination in vitro and in vivo

Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

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