Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Guo, Yunhang; Liu, Ye; Hu, Nan; Yu, Desheng; Zhou, Changyou; Shi, Gongyin; Zhang, Bo; Min, Wei; Liu, Junhua; Luo, Liang; Tang, Zhiyu; Song, Huipeng; Guo, Yin; Liu, Xuesong; Su, Dan; Zhang, Shuo; Song, Xiaomin; Zhou, Xing; Yuan, Hong; Chen, Shuaishuai; Cheng, Zhengxing; Young, Steve; Wei, Qiang; Wang, Haisheng; Wang, Qiuwen; Lv, Lei; Wang, Fan; Xu, Haipeng; Sun, Hanzi; Xing, Haimei; Li, Na; Zhang, Wei; Wang, Zhongbo; Liu, Guodong; Sun, Zhijian; Zhou, Dongping; Li, Wei; Liu, Libin; Wang, Lai; Wang, Zhiwei

doi:10.1021/acs.jmedchem.9b00687

Cited by 240 publications

(280 citation statements)

References 41 publications

(64 reference statements)

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“…However, zanubrutinib is more selective than ibrutinib against off-target kinases, including epidermal growth factor receptor, Janus tyrosine kinase 3, human epidermal growth factor receptor 2, Tec protein-tyrosine kinase, and inducible tyrosine kinase. 6 The increased selectivity of zanubrutinib for BTK may result in a lower incidence and severity of off-target toxicities linked to inhibition of the aforementioned kinases. Emerging clinical data have shown that zanubrutinib as a single agent and in combination with other therapies resulted in high rates of objective response in patients with B-cell malignancies, including Waldenström's macroglobulinemia, MCL, and chronic lymphocytic leukemia, 7-9 consistent with its near-complete BTK occupancy and target engagement in target tissues (median occupancy of 100% in lymph nodes).…”

Section: How Might This Change Clinical Pharmacol-ogy or Translationamentioning

confidence: 99%

No QTc Prolongation With Zanubrutinib: Results of Concentration‐QTc Analysis From a Thorough QT Study in Healthy Subjects

Mu¹,

Darpö²,

Tang³

et al. 2020

Clinical Translational Sci

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This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration‐QTc (C‐QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo‐controlled and positive‐controlled, four‐way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open‐label moxifloxacin 400 mg. Thirty‐two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T‐wave morphology) and was generally well‐tolerated. Using C‐QTc analysis, the predicted placebo‐corrected change‐from‐baseline QT interval using Fridericia’s formula (ΔΔQTcF) was −3.4 msec (90% confidence interval: −4.9 to −1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C‐QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time‐point analysis. A single 160‐mg or 480‐mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.

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Section: How Might This Change Clinical Pharmacol-ogy or Translationamentioning

confidence: 99%

No QTc Prolongation With Zanubrutinib: Results of Concentration‐QTc Analysis From a Thorough QT Study in Healthy Subjects

Mu¹,

Darpö²,

Tang³

et al. 2020

Clinical Translational Sci

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“…4 Zanubrutinib (BGB-3111) is a highly specific second-generation BTKi, with favorable oral bioavailability seen in preclinical studies. 5,6 Compared with ibrutinib, zanubrutinib has shown greater selectivity for BTK with fewer off-target effects based on multiple in vitro enzymatic and cell-based assays (see supplemental Table 1 in Tam et al 7 ). In a recent head-to-head phase 3 comparison in Waldenström macroglobulinemia (WM), zanubrutinib treatment was associated with less toxicity, particularly cardiovascular toxicity, and a trend toward better response quality.…”

Section: Introductionmentioning

confidence: 99%

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma

Tam

Quach

Nicol³

et al. 2020

Blood Advances

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Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

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“…The aberrant activation of Bruton tyrosine kinase has a key role in the tumorigenesis of B-cell lymphoma ( Guo et al 2019 ). Its abrogation seems to protect lungs from acute immune-induced or lethal influenza-induced injuries ( Florence et al 2018 ; Krupa et al 2014 ) as well as sepsis-induced injury ( Zhou et al 2014 ).…”

Section: Potential Anticancer Drugs For Covid-19mentioning

confidence: 99%

Repurposing anticancer drugs for the management of COVID-19

Bairi

Trapani

Petrillo

et al. 2020

European Journal of Cancer

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Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion, thus regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been largely applied for early clinical testing. In this Review , we discuss some repurposed anticancer drugs for the treatment of COVID-19 and under investigation in clinical trials or proposed for the clinical testing. .

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Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Cited by 240 publications

References 41 publications

No QTc Prolongation With Zanubrutinib: Results of Concentration‐QTc Analysis From a Thorough QT Study in Healthy Subjects

No QTc Prolongation With Zanubrutinib: Results of Concentration‐QTc Analysis From a Thorough QT Study in Healthy Subjects

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma

Repurposing anticancer drugs for the management of COVID-19

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