Anti-Cancer Drugs Acalabrutinib

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Anti-Cancer Drugs Acalabrutinib

Acalabrutinib Reviews Acalabrutinib (CAS:1420477-60-6), which is marketed under the tradename of Calquence® in the U.S. and Canada, is a second-generation small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Upon oral administration, acalabrutinib binds to and irreversibly inhibits the activity of BTK which prevents both B-cell activation and B-cell-mediated signaling. This action leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is required for B-cell signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies, including CLL/SLL. The expression of BTK in tumor cells is associated with increased proliferation and survival. As a second-generation BTK inhibitor, acalabrutinib was designed to maximize the effect on BTK and minimize off-target activity on TEC (Tec Protein Tyrosine Kinase), EGFR (epidermal growth factor receptor), and ITK (interleukin-2-inducible T-cell kinase). The first generation BTK inhibitor, ibrutinib (Imbruvica), lacks this specificity which results in a higher incidence of adverse effects. In addition to CLL/SLL, acalabrutinib is approved for Mantle Cell Lymphoma (MCL).

The National Cancer Center Network (NCCN) Guidelines list acalabrutinib with or without obinituzumab as first line therapy for CLL/SLL as well as appropriate for use in relapsed or refractory (R/R) CLL.

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Acalabrutinib Treatment(Used for) Acalabrutinib is used to treat people with mantle cell lymphoma (MCL; a fast-growing cancer that begins in the cells of the immune system) who have already been treated with at least one other chemotherapy medication.

Acalabrutinib is used alone or with obinutuzumab (Gazyva) to treat chronic lymphocytic leukemia (CLL; a type of cancer that begins in the white blood cells) and small lymphocytic lymphoma (SLL: a type of cancer that begins in the white blood cells).

Acalabrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.

Acalabrutinib Mechanism Of Action Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression.

Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body’s own B-lymphocytes (B-cells).

Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling 2

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causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity.As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival.

Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor,acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.

In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects – in theory – because of the drug’s minimized off target effects.

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