Acalabrutinib
[CAS# 1420477-60-6]

Identification

• Classification: API >> Circulatory system medication
• Name: Acalabrutinib
• Synonyms: 4-[8-Amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinylbenzamide; ACP 196
• Molecular Formula: C₂₆H₂₃N₇O₂
• Molecular Weight: 465.51
• CAS Registry Number: 1420477-60-6
• EC Number: 814-272-0
• SMILES: CC#CC(=O)N1CCC[C@H]1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5

Properties

• Solubility: Insoluble (1.3E^-3 g/L) (25 °C), Calc.^*
• Density: 1.37±0.1 g/cm³ (20 °C 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08 Warning
• Risk Statements: H373
• Safety Statements: P260-P319-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - repeated exposure	STOT RE	2	H373

Discovery and Applications

Acalabrutinib is a selective Bruton's tyrosine kinase (BTK) inhibitor that has been developed as a therapeutic agent for the treatment of various hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and other B-cell lymphomas. The drug was discovered as part of the ongoing search for targeted therapies in cancer treatment, particularly for cancers involving B cells, which play a central role in many immune-related diseases. By selectively inhibiting BTK, Acalabrutinib disrupts critical signaling pathways that are involved in the proliferation and survival of B cells, thus offering a potential treatment option for patients with these malignancies.

The discovery of Acalabrutinib was motivated by the need for a more specific and less toxic alternative to other BTK inhibitors such as ibrutinib. While ibrutinib has proven effective in treating various B-cell malignancies, it is associated with side effects such as atrial fibrillation and bleeding, which are related to its non-selectivity for BTK. Acalabrutinib was designed to overcome these limitations by providing a more selective inhibition of BTK, minimizing off-target effects and improving the drug's safety profile. The development of Acalabrutinib involved the identification of novel molecular compounds that specifically target the BTK enzyme, leading to its inhibition and subsequent disruption of the B-cell receptor signaling pathway.

Acalabrutinib has shown significant promise in clinical trials, particularly for patients with CLL and MCL, where it has demonstrated the ability to significantly reduce tumor burden and improve progression-free survival. The drug works by binding to the BTK enzyme and irreversibly inhibiting its activity. This blockade prevents the downstream signaling that is crucial for the survival and proliferation of malignant B cells. In addition to its effectiveness in treating CLL and MCL, Acalabrutinib is also being explored for its potential in other B-cell malignancies, including Waldenström’s macroglobulinemia and diffuse large B-cell lymphoma (DLBCL).

One of the key advantages of Acalabrutinib over older BTK inhibitors is its improved selectivity, which reduces the occurrence of adverse events such as bleeding complications and cardiovascular issues. Clinical studies have shown that Acalabrutinib is well tolerated, with a side effect profile that is more favorable compared to ibrutinib. This makes it an attractive option for long-term therapy, particularly for patients who may be at higher risk of complications from other treatments. Furthermore, Acalabrutinib’s oral bioavailability and once-daily dosing regimen make it a convenient option for patients, improving patient compliance and overall quality of life.

Beyond its established applications in CLL and MCL, ongoing research is focused on exploring Acalabrutinib’s potential in combination with other therapies for the treatment of B-cell malignancies. The drug is also being investigated in clinical trials for its potential use in autoimmune diseases, where B-cell activation plays a central role in disease pathogenesis.

Acalabrutinib represents a significant advancement in the treatment of B-cell malignancies, offering a targeted and effective therapy with a more favorable safety profile compared to previous BTK inhibitors. As research continues, Acalabrutinib could play a central role in the evolving landscape of cancer treatment, particularly for patients with resistant or relapsed forms of B-cell cancers.

References

2024. Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia. Nature Reviews. Clinical Oncology, 21(12).
DOI: 10.1038/s41571-024-00956-1

2024. Acalabrutinib alone or in combination with rituximab for follicular lymphoma: An open-label study. British Journal of Haematology, 206(6).
DOI: 10.1111/bjh.19787

2016. Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton’s tyrosine kinase inhibitors. Bioorganic & Medicinal Chemistry Letters, 26(13).
DOI: 10.1016/j.bmcl.2016.05.014