acalabrutinib   

GtoPdb Ligand ID: 8912

Synonyms: ACP-196 | Calquence® | Example 6 [US20140155385 A1] [2]
acalabrutinib is an approved drug (FDA (2017))
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.
2D Structure
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Physico-chemical Properties
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
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
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.

In response to the SARS-CoV-2 pandemic plans are underway to evaluate acalabrutinib in COVID-19 patients, as part of the UK's Accelerating COVID-19 Research and Development (ACCORD) initiative (June 2020). ACCORD aims to fast-track potential treatments for COVID-19 through early-stage clinical trials [5]. In this setting researchers would aim to determine if the anti-inflammatory action of BTK-inhibition has efficacy to reduce mortality in patients with severe COVID-19.
Mechanism Of Action and Pharmacodynamic Effects
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