Zanubrutinib
Overview
Description
Zanubrutinib, marketed under the brand name Brukinsa, is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor. It is primarily used for the treatment of various B-cell malignancies, including mantle cell lymphoma, Waldenström’s macroglobulinemia, marginal zone lymphoma, and chronic lymphocytic leukemia . This compound has shown significant efficacy and safety improvements over first-generation BTK inhibitors, making it a promising option for patients with these conditions .
Mechanism of Action
Target of Action
Zanubrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor . BTK is an enzyme that plays a crucial role in oncogenic signaling pathways, promoting the survival and proliferation of malignant B cells .
Mode of Action
This compound works by binding to the active site of BTK, thereby inhibiting its function . This inhibition blocks the activity of BTK, which is associated with malignant B-cell growth and survival . Compared to the first-generation BTK inhibitor ibrutinib, this compound displays higher potency and selectivity for BTK with fewer off-target effects .
Biochemical Pathways
This compound affects multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions . It inhibits the B-cell receptor (BCR) signaling pathway, leading to the activation of NF-κB and related pathways . This inhibition results in the hampering of pre-BCR signaling and B cell development .
Pharmacokinetics
This compound was developed using a structure-activity strategy to enhance its specificity as well as enzymatic and pharmacokinetic properties . It has better bioavailability compared to ibrutinib . The mean half-life of this compound is approximately 2–4 hours after a single oral dose of 160 or 320 mg, and the geometric mean apparent oral clearance is 182 L/h .
Result of Action
This compound effectively inhibits the phosphorylation of proteins in the ERBB signaling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells . It reduces the tumor size in mantle cell lymphoma by decreasing the survival of malignant B cells .
Action Environment
The efficacy and safety of this compound can be influenced by various factors. For instance, mutations in MYD88, TNFAIP3, and KMT2D can affect the progression-free survival in patients with relapsed/refractory marginal zone lymphoma treated with this compound . Additionally, the presence of acquired BTK and PLCG2 mutations in circulating tumor cell–free DNA while on therapy may herald clinical disease progression .
Biochemical Analysis
Biochemical Properties
Zanubrutinib plays a crucial role in biochemical reactions by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme involved in B-cell receptor signaling . This inhibition disrupts the survival and proliferation of malignant B cells. This compound interacts specifically with BTK by binding to its active site, leading to the inhibition of downstream signaling pathways that promote cell survival and proliferation . Compared to first-generation BTK inhibitors like ibrutinib, this compound exhibits higher selectivity for BTK with fewer off-target effects .
Cellular Effects
This compound exerts significant effects on various types of cells, particularly B cells. By targeting BTK, this compound impairs cell proliferation, migration, and activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) . This inhibition leads to reduced cell survival and proliferation in malignant B cells. Additionally, this compound influences cell signaling pathways, gene expression, and cellular metabolism, contributing to its therapeutic efficacy in B-cell malignancies .
Molecular Mechanism
At the molecular level, this compound exerts its effects by binding covalently to the active site of BTK, thereby inhibiting its kinase activity . This binding prevents the phosphorylation of downstream signaling molecules, ultimately leading to the inhibition of B-cell receptor signaling pathways . The inhibition of BTK by this compound results in decreased activation of NF-κB and other transcription factors, reducing the expression of genes involved in cell survival and proliferation .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound have been observed to change over time. Studies have shown that this compound maintains its stability and potency over extended periods . Long-term exposure to this compound can lead to the development of resistance in some cases . Additionally, the degradation of this compound and its metabolites has been studied to understand its long-term effects on cellular function .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. Studies have demonstrated that this compound is well-tolerated at therapeutic doses, with minimal toxic or adverse effects . At higher doses, this compound can cause toxic effects, including hematological toxicity and liver damage . These findings highlight the importance of optimizing dosage to achieve therapeutic efficacy while minimizing adverse effects .
Metabolic Pathways
This compound is primarily metabolized by cytochrome P450 (CYP)3A in the liver . The metabolic pathways of this compound involve oxidation and subsequent conjugation reactions, leading to the formation of various metabolites . These metabolites are then excreted through the urine and feces . The interaction of this compound with metabolic enzymes and cofactors plays a crucial role in determining its pharmacokinetic properties and overall efficacy .
Transport and Distribution
This compound is transported and distributed within cells and tissues through passive diffusion and active transport mechanisms . It interacts with various transporters and binding proteins, which facilitate its uptake and distribution . The localization and accumulation of this compound within specific tissues and compartments are influenced by these interactions, contributing to its therapeutic effects .
Subcellular Localization
The subcellular localization of this compound is primarily within the cytoplasm, where it interacts with BTK and other signaling molecules . This compound does not require specific targeting signals or post-translational modifications for its localization . Its activity and function are determined by its ability to bind to BTK and inhibit its kinase activity within the cytoplasm .
Preparation Methods
The synthesis of zanubrutinib involves several key steps. One of the primary synthetic routes includes the coupling of a phenoxyphenyl derivative with a piperidinyl-pyrazolopyrimidine intermediate. The final product is obtained through chiral high-performance liquid chromatography (HPLC) separation . Industrial production methods focus on optimizing yield, chemical purity, and optical purity, ensuring the compound is suitable for large-scale manufacturing .
Chemical Reactions Analysis
Zanubrutinib undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized under specific conditions, leading to the formation of degradation products.
Reduction: The compound can also undergo reductive stress, resulting in different degradation products.
Substitution: Substitution reactions can occur, particularly involving the phenoxyphenyl moiety.
Common reagents used in these reactions include acids, bases, and oxidizing agents. The major products formed from these reactions are typically degradation products that are analyzed to ensure the stability and efficacy of the compound .
Scientific Research Applications
Zanubrutinib has a wide range of scientific research applications:
Chemistry: It is used as a model compound for studying BTK inhibition and its effects on B-cell receptor signaling pathways.
Biology: this compound is utilized in research to understand the role of BTK in various cellular processes, including immune response and cell proliferation.
Comparison with Similar Compounds
Zanubrutinib is often compared with other BTK inhibitors, such as ibrutinib and acalabrutinib. While all three compounds target BTK, this compound has shown higher selectivity and potency, resulting in fewer off-target effects and improved safety profiles . Additionally, this compound provides continuous exposure above its inhibitory concentration, enhancing its efficacy .
Similar Compounds
Ibrutinib: The first-generation BTK inhibitor with broader off-target effects.
Acalabrutinib: Another second-generation BTK inhibitor with a different safety and efficacy profile compared to this compound.
Properties
IUPAC Name |
(7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C27H29N5O3/c1-2-23(33)31-16-13-18(14-17-31)22-12-15-29-27-24(26(28)34)25(30-32(22)27)19-8-10-21(11-9-19)35-20-6-4-3-5-7-20/h2-11,18,22,29H,1,12-17H2,(H2,28,34)/t22-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
RNOAOAWBMHREKO-QFIPXVFZSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C=CC(=O)N1CCC(CC1)C2CCNC3=C(C(=NN23)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=O)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C=CC(=O)N1CCC(CC1)[C@@H]2CCNC3=C(C(=NN23)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=O)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C27H29N5O3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID701026208 |
Source
|
| Record name | Zanubrutinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID701026208 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
471.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Bruton's tyrosine kinase (BTK) is a non-receptor kinase and a signalling molecule for the B cell receptors expressed on the peripheral B cell surface. The BCR signalling pathway plays a crucial role in normal B-cell development but also the proliferation and survival of malignant B cells in many B cell malignancies, including mantle-cell lymphoma (MCL). Once activated by upstream Src-family kinases, BTK phosphorylates phospholipase-Cγ (PLCγ), leading to Ca2+ mobilization and activation of NF-κB and MAP kinase pathways. These downstream cascades promote the expression of genes involved in B cell proliferation and survival. The BCR signalling pathway also induces the anti-apoptotic protein Bcl-xL and regulates the integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin via BTK. Apart from the direct downstream signal transduction pathway of B cells, BTK is also involved in chemokine receptor, Toll-like receptor (TLR) and Fc receptor signalling pathways. Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue in the adenosine triphosphate (ATP)–binding pocket of BTK, which is the enzyme's active site. This binding specificity is commonly seen with other BTK inhibitors. Due to this binding profile, zanubrutinib may also bind with varying affinities to related and unrelated ATP-binding kinases that possess a cysteine residue at this position. By blocking the BCR signalling pathway, zanubrutinib inhibits the proliferation, trafficking, chemotaxis, and adhesion of malignant B cells, ultimately leading to reduced tumour size. Zanubrutinib was also shown to downregulate programmed death-ligand 1 (PD-1) expression and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on CD4+ T cells. |
Source
|
| Record name | Zanubrutinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB15035 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
1691249-45-2 |
Source
|
| Record name | (7S)-4,5,6,7-Tetrahydro-7-[1-(1-oxo-2-propen-1-yl)-4-piperidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=1691249-45-2 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Zanubrutinib [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1691249452 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Zanubrutinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB15035 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Zanubrutinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID701026208 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | ZANUBRUTINIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/AG9MHG098Z | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Disclaimer and Information on In-Vitro Research Products
Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
![[(1S,5R)-8-methyl-8-[(4-phenylphenyl)methyl]-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate](/img/structure/B611845.png)
