Discussion on the therapeutic effect and working principle of ensidipine

Enasidenib is a targeted drug for specific types of leukemia. It is mainly used to treat patients with acute myeloid leukemia (AML) who have IDH2 gene mutations. This drug specifically inhibits the activity of IDH2 enzyme and interferes with the abnormal protein produced by IDH2 gene mutation, thereby interfering with the growth and division of AML cells.

IDH2The enzyme participates in redox reactions during cell metabolism under normal circumstances, converting isocitrate into α-ketoglutarate, thereby generating NADPH, which is an important reducing agent that can protect cells from oxidative stress damage. However, in the leukemia cells of some AML patients, the IDH2 gene undergoes mutations, resulting in abnormal enzyme activity and converting α -Ketoglutarate is converted into isocitrate and produces an abnormal metabolite - 2-hydroxyglutarate (2-HG). 2-HGAs a tumor-promoting factor, it can inhibit cell differentiation, promote cell proliferation, induce abnormal gene expression, interfere with DNA and histone modifications, and activate cancer-related signaling pathways. Therefore, IDH2mutation is a driver of AML and a poor prognostic indicator.

The principle of action of ensidipine is to reduce the level of 2-HG by inhibiting the mutated IDH2 enzyme, thereby restoring normal cell differentiation, inhibiting the growth of leukemia cells, inducing apoptosis of leukemia cells, and reversing cancer-related epigenetic changes. Ensidipine can highly selectively bind to the active site of IDH2, block its catalytic activity, and effectively inhibit the synthesis of 2-HG. This inhibitory effect effectively controls the accumulation of 2-HG in leukemia cells, helping to restore the normal metabolic state of the cells.

In clinical studies, ensidipine has performed well, with significant efficacy and high safety. Multiple clinical trials have shown that ensidipine is effective in treating IDH2 mutant acute myeloid leukemia (AML) and drugs containing IDH2mutated myelodysplastic syndrome (MDS), it can significantly improve the patient's survival rate and relieve symptoms, delay disease progression, and improve the overall prognosis of the patient. For example, the results of a clinical trial called AG221-001 showed that the objective response rate (ORR) of ensidipine reached 40.8%, the median duration of response was 19.4 months, and the median overall survival (OS) was 9.3 months.

In addition, the use of ensidipine can also promote the differentiation and maturation of leukemia cells by reducing the accumulation of 2-HG, thereby further inhibiting the development of leukemia. Common adverse reactions of ensidipine include nausea, vomiting, diarrhea, loss of appetite, increased bilirubin, etc., but they can generally be alleviated by adjusting dosage, monitoring indicators, and symptomatic treatment.

References:

https://www.dovepress.com/enasidenib-in-the-treatment-of-relapsedrefractory-acute-myeloid-leukem-peer-reviewed-fulltext-article-CE