acalabrutinib   Click here for help

GtoPdb Ligand ID: 8912

Synonyms: ACP-196 | Calquence® | Example 6 [US20140155385 A1] [2]
Approved drug PDB Ligand Immunopharmacology Ligand
acalabrutinib is an approved drug (FDA (2017), EMA (2020))
Compound class: Synthetic organic
Comment: Acalabrutinib is an orally available second-generation, selective and irreversible inhibitor of Bruton tyrosine kinase (BTK) [6], being investigated for its potential antineoplastic activity (in multiple haematologic malignancies and solid tumours), as well as a potential therapy for rheumatoid arthritis. Acalabrutinib covalently bonds to Cysteine-481 in BTK.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 118.51
Molecular weight 465.19
XLogP 4.09
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CC#CC(=O)N1CCCC1c1nc(c2n1ccnc2N)c1ccc(cc1)C(=O)Nc1ccccn1
Isomeric SMILES CC#CC(=O)N1CCC[C@H]1c1nc(c2n1ccnc2N)c1ccc(cc1)C(=O)Nc1ccccn1
InChI InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1
InChI Key WDENQIQQYWYTPO-IBGZPJMESA-N
No information available.
Summary of Clinical Use Click here for help
Having already received FDA Orphan Drug Designation and Breakthrough Therapy Designation for mantle cell lymphoma (MCL: a rare and fast-growing type of non-Hodgkin lymphoma), in August 2017 the FDA granted priority review for acalabrutinib's New Drug Application (NDA), based on results from a Phase 2 study in relapsed/refractory MCL (NCT02213926). This resulted in full FDA approval in October 2017 (link to FDA announcement). This approval is for the treatment of MCL patients who have received at least one prior therapy.

For a list of all registered acalabrutinib trials, link here to ClinicalTrials.gov.

In November 2019, FDA approval was expanded to include treatment of CLL or SLL, following evaluation in trials including NCT02475681 and NCT02970318; clinial trial results in patients with CLL are reported in [4], [3] and [1].

Trials to assess acalabrutinib's efficacy in a variety of solid tumours (such as bladder, prostate and non-small cell lung cancers) are ongoing.

In the European Union, the EMA has granted acalabrutinib orphan designation for three rare diseases (as of 2016): CLL/SLL, lymphoplasmacytic lymphoma and MCL.

SARS-CoV-2 and COVID-19: In response to the SARS-CoV-2 pandemic acalabrutinib was evaluated in COVID-19 patients, as part of the UK's Accelerating COVID-19 Research and Development (ACCORD) initiative (June 2020). ACCORD is designed to fast-track potential treatments for COVID-19 through early-stage clinical trials [5]. In this setting researchers would aimed to determine if the anti-inflammatory action of BTK-inhibition has efficacy to reduce mortality in patients with severe COVID-19. In November 2020, AstraZeneca announced that acalabrutinib missed its primary endpoint in Phase 2, and failed to "increase the proportion of patients who remained alive and free of respiratory failure".
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Under normal conditions BTK plays an important role in B lymphocyte development, activation, signalling, proliferation and survival, via activation of the B cell antigen receptor (BCR) signalling pathway. BTK is overexpressed in a significant proportion of B cell malignancies. The survival and proliferation of these malignant B cells can be blocked by small-molecule BTK inhibitors.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02213926 An Open-label, Phase 2 Study of ACP-196 (Acalabrutinib) in Subjects With Mantle Cell Lymphoma Phase 2 Interventional Acerta Pharma BV
NCT02475681 Elevate CLL TN: Study of Obinutuzumab + Chlorambucil, Acalabrutinib (ACP-196) + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL Phase 3 Interventional Acerta Pharma BV
NCT02970318 A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL Phase 3 Interventional Acerta Pharma BV
NCT04346199 Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. Phase 2 Interventional AstraZeneca
NCT04380688 Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. Phase 2 Interventional AstraZeneca