Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

Rhodes, Joanna; Mato, Anthony R.

doi:10.2147/dddt.s250823

Cited by 10 publications

(7 citation statements)

References 56 publications

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“…These results indicate that sonrotoclax has more potent antitumor activity than venetoclax in preclinical models of multiple hematologic cancers. Furthermore, the combination of sonrotoclax and zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, 40 , 41 showed significantly stronger antitumor activity than either single agent in the JeKo-1 xenograft model ( supplemental Figure 4 ), indicating a potential utility of sonrotoclax in combination therapy.…”

Section: Resultsmentioning

confidence: 99%

Sonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models of hematologic malignancy

Liu,

Li,

Wang

et al. 2024

Blood

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Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and pro-apoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia (CLL) and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in relapsed patients treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. Herein, we discovered sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematological cancer cells and more profound tumor growth inhibition in multiple hematological tumor models compared to venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type (WT) BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

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Section: Resultsmentioning

confidence: 99%

Sonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models of hematologic malignancy

Liu,

Li,

Wang

et al. 2024

Blood

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“…Zanubrutinib is associated with an overall favorable safety profile, with a low incidence of major bleeding or arrythmias observed in patients with CLL ( 60 ). The National Comprehensive Cancer Network guidelines recommend the use of zanubrutinib as a first-line or second-line therapy for patients with CLL/SLL with del(17p)/ TP53 mutations who have a contraindication to other BTK inhibitors, and as second-line and subsequent therapy for patients without del(17p)/ TP53 mutations who are intolerant of, or have a contraindication to, other BTK inhibitors ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

O’Brien¹,

Brown

Byrd

et al. 2021

Front. Oncol.

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Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

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“…Zanubrutinib inhibits BTK irreversibly with similar affinity as ibrutinib, but shows significantly decreased affinity to other kinases that contain a cysteine at the ATP-binding site [ 100 , 101 ]. The relatively high affinity of ibrutinib to other kinases seems to be responsible for its off-target effects that include bleeding, atrial fibrillation, rash, and diarrhea [ 102 , 103 , 104 ]. Zanubrutinib is much more specific for BTK; therefore, it is thought to be associated with fewer toxicities.…”

Section: Investigational Approaches and Perspectivesmentioning

confidence: 99%

Current Treatment Options in CLL

Bewarder

Stilgenbauer

Thurner

et al. 2021

Cancers

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After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients. Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3 kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the determination of the optimal combination and sequence of those drugs. Here, we give an overview of current treatment options in CLL, weighing the advantages and disadvantages of each approach in the light of different clinical settings.

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Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

Cited by 10 publications

References 56 publications

Sonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models of hematologic malignancy

Sonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models of hematologic malignancy

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

Current Treatment Options in CLL

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