scholarly journals Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

2020 ◽  
Vol 86 (9) ◽  
pp. 1849-1859 ◽  
Author(s):  
Ian M. Catlett ◽  
Miroslawa Nowak ◽  
Sudeep Kundu ◽  
Naiyu Zheng ◽  
Ang Liu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Controlled Trial ◽  
Bruton’S Tyrosine Kinase ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Irreversible Inhibitor ◽  
Bruton's Tyrosine Kinase ◽  
Healthy Participants

scholarly journals Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase

2020 ◽  
Vol 21 (21) ◽  
pp. 8006
Author(s):  
Eun Lee ◽  
Hyewon Cho ◽  
Da Kyung Lee ◽  
JuHyun Ha ◽  
Byeong Jo Choi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Unmet Need ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Type Ii ◽  
Irreversible Inhibitor ◽  
Bruton's Tyrosine Kinase ◽  
Irreversible Inhibitors ◽  
Btk Inhibitors

As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure–activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.

scholarly journals A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers

2017 ◽  
Vol 83 (11) ◽  
pp. 2367-2376 ◽  
Author(s):  
Patrick F. Smith ◽  
Janakan Krishnarajah ◽  
Philip A. Nunn ◽  
Ron J. Hill ◽  
Dane Karr ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Healthy Volunteers ◽  
Phase I Trial ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Reversible Covalent ◽  
Covalent Inhibitor

scholarly journals Mir-155 Expression Is Associated with Chemoimmunotherapy Outcome and Is Modulated By Bruton’s Tyrosine Kinase Inhibition with Ibrutinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3297-3297 ◽  
Author(s):  
Daphne Guinn ◽  
Amy S. Ruppert ◽  
Kami J. Maddocks ◽  
Samantha Jaglowski ◽  
Amber L. Gordon ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Research Funding ◽  
Close Association ◽  
Lymphocytic Leukemia ◽  
Bruton’S Tyrosine Kinase ◽  
Irreversible Inhibitor ◽  
Persistent Lymphocytosis ◽  
Bruton's Tyrosine Kinase ◽  
Risk Of Death ◽  
Pre Treatment

Abstract Overexpression of the oncomiR, miR-155, is known to be predictive of poor outcome in chronic lymphocytic leukemia (CLL) patients. Using NanoString Technologies’ nCounter platform, we interrogated the miR-155 expression levels in 109 previously untreated CLL patients receiving chemoimmunotherapy on CALGB 9712 or CALGB 10101. The data, dichotomized around median expression, showed that high expressers of miR-155 had shorter progression-free survival (p=0.005) and a higher risk of death after 4 years on study (p=0.004). The expression of miR-155 was not significantly associated with the majority of baseline demographic, clinical and cytogenetic characteristics, including age, Rai stage and high-risk cytogenetics [del(17p)/del(11q)] (p>0.15). Association of high miR-155 expression with IGHV un-mutated disease(p=0.03) and ZAP70 methylation <20% (p<0.001) were also confirmed with this data. Previously, associations have been made between IGHV unmutated status/high ZAP70 levels and a B cell receptor (BCR) activated phenotype. Therefore, to investigate the close association between BCR activation and miR-155 in CLL, we explored regulation of BCR pathways through ibrutinib-mediated inhibition of Bruton’s tyrosine kinase (BTK) and its ability to modulate miR-155. Ibrutinib is an irreversible inhibitor of BTK, an integral kinase in the BCR pathway, and ibrutinib treatment has been shown to decrease pro-survival signaling via the AKT, ERK and NFκB pathways. Serial samples from ibrutinib-treated (420 mg/day) patients were obtained pre-treatment and on days 8 and 29 of therapy on the Phase Ib/II trial OSU-10053 (n=12). miR-155 expression, interrogated using real time PCR (RT-PCR), was significantly lower pre-treatment versus day 8 (p<0.001) and day 29 (P=0.0010). In a confirmatory set of 34 samples from patients treated on the Phase II trial OSU-11133 (NCT01589302), miR-155 expression was 0.71-fold the expression prior to therapy (95% CI: 0.59-0.85, p=0.0006). miR-155 expression was down-regulated at day 29 in 29 (85%) of the patients studied. The response pattern observed with ibrutinib includes traditional partial and complete responses However, some patients receiving ibrutinib exhibit dramatic nodal disease reduction with persistent lymphocytosis in the blood and remain asymptomatic for an extended period of time without evidence of active proliferation. In contrast, patients who relapse after responding to ibrutinib typically have proliferative disease. In patients treated with ibrutinib that had a partial response with persistent lymphocytosis at 1 year, miR-155 expression remained down-modulated relative to pre-treatment levels (p=0.013). However, levels of miR-155 were significantly elevated relative to baseline in samples from relapsed patients (p=0.002). We therefore conclude not only that miR-155 expression is predictive of disease progression after chemoimmunotherapy in CLL, but that this important oncomiR can be favorably down-modulated by ibrutinib treatment. Disclosures Jaglowski: Pharmacyclics: Research Funding. Lin:GlaxoSmithKline: Employment, Equity Ownership. Byrd:Pharmacyclics: Research Funding; Genentech: Research Funding.

ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation

2018 ◽  
Vol 29 (3) ◽  
pp. 510-522 ◽  
Author(s):  
Christian Goess ◽  
Christopher M. Harris ◽  
Sara Murdock ◽  
Richard W. McCarthy ◽  
Erik Sampson ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Preclinical Models ◽  
Irreversible Inhibitor ◽  
Bruton's Tyrosine Kinase

scholarly journals Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma

2020 ◽  
Author(s):  
Yoshitaka Narita ◽  
Motoo Nagane ◽  
Kazuhiko Mishima ◽  
Yasuhito Terui ◽  
Yoshiki Arakawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Central Nervous System Lymphoma ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase

Abstract Background The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). Methods Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. Results Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. Conclusion These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. Trial registration JapicCTI-173646.

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