AZD5991 is an investigational drug being explored for its potential in treating certain cancers. It represents a targeted approach to cancer therapy, aiming to interfere with specific processes that allow cancer cells to survive and multiply. This compound is a small molecule designed to interact with proteins involved in cell survival pathways.
How AZD5991 Works
AZD5991 functions as a selective inhibitor of myeloid cell leukemia-1 (MCL-1), a protein belonging to the BCL-2 family. The BCL-2 family of proteins regulates apoptosis, the body’s natural process of programmed cell death. MCL-1 specifically promotes cell survival by preventing apoptosis in many cancer types.
By directly binding to MCL-1, AZD5991 disrupts MCL-1’s ability to prevent programmed cell death. This action leads to the activation of the mitochondrial apoptotic pathway, causing cancer cells to undergo rapid apoptosis. Preclinical studies indicate that AZD5991 has a high potency for human MCL-1, with an IC50 of 0.7 nM in FRET assays and a Kd of 0.17 nM in surface plasmon resonance assays. The compound also shows significant selectivity, with a binding affinity more than 10,000-fold lower for other BCL-2 family members.
Conditions Targeted by AZD5991
AZD5991 is primarily being investigated for its potential in treating hematological malignancies, which are cancers affecting blood, bone marrow, and lymph nodes. Research has focused particularly on acute myeloid leukemia (AML) and multiple myeloma (MM). These cancers often rely on MCL-1 for their survival, making them potential targets for this inhibitor.
Preclinical studies have shown that AZD5991 monotherapy can cause apoptosis preferentially in many hematological cell lines, including AML and MM. The drug has also demonstrated ex vivo activity in primary cells from patients with MM. Beyond AML and MM, enhanced antitumor activity has been observed in vitro and in vivo models of non-Hodgkin lymphoma (NHL) when AZD5991 is combined with venetoclax.
Where AZD5991 Stands in Development
AZD5991 has progressed to clinical development, with a Phase 1 study initiated to evaluate its safety, tolerability, and preliminary antitumor activity. This study included patients with relapsed or refractory hematologic malignancies, administered as monotherapy or in combination with venetoclax. The monotherapy cohort involved 61 patients receiving intravenous AZD5991, while 17 patients with acute myeloid leukemia and myelodysplastic syndrome received it in combination with venetoclax.
The clinical trial reported common adverse events, including diarrhea, nausea, and vomiting. Grade 3 or higher adverse events were also reported, with febrile neutropenia and anemia being common hematologic events. While preclinical data showed promise, the Phase 1 study indicated limited clinical activity across various hematologic malignancies, with some objective responses observed in myelodysplastic syndrome. A notable safety concern was frequent asymptomatic troponin elevations, which led to the early termination of the study due to the overall risk-benefit profile. This underscores that AZD5991 is an investigational drug and is not approved for general clinical use.