AZD3965 is an investigational drug compound currently undergoing research for its potential in treating various cancers. Developed by AstraZeneca PLC, it targets specific metabolic pathways within cancer cells. It is currently in preclinical and Phase 1 development, exploring its safety and initial effectiveness. This approach aims to disrupt how cancer cells obtain energy, offering a new therapeutic strategy. Studies are focused on understanding its capabilities and how it might integrate into future cancer treatments.
What is AZD3965?
AZD3965 is a pyrrole pyrimidine derivative, identified by its CAS number 1448671-31-5 and molecular formula C21H24F3N5O5S. It functions as a monocarboxylate transporter 1 (MCT1) inhibitor. Its purpose is to interfere with metabolic processes that support cancer cell growth and survival.
It is an orally available small molecule with a high binding affinity of 1.6 nM for MCT1. While it primarily targets MCT1, it exhibits six-fold selectivity over MCT2 and no inhibitory activity against MCT3 or MCT4 at concentrations up to 10 µM. This specificity focuses its therapeutic effects on cancer cells that rely heavily on MCT1 for their metabolic needs.
How AZD3965 Works
Cancer cells often exhibit the Warburg effect, preferentially using glycolysis for energy production, even in the presence of oxygen. This process generates lactate. To prevent cellular acidosis from lactate buildup, cancer cells often upregulate monocarboxylate transporters (MCTs) to extrude lactate.
AZD3965 works by inhibiting MCT1, a protein that transports lactate across cell membranes. By blocking MCT1, AZD3965 prevents lactate efflux from cancer cells, leading to intracellular lactate accumulation. This intracellular lactate buildup can make the cell’s internal environment acidic, disrupting normal cellular functions and ultimately leading to cancer cell death.
This inhibition also impacts cancer cell energy metabolism. When lactate cannot be removed, it can lead to feedback inhibition of glycolysis, a primary energy production pathway for many cancer cells. MCT1 inhibition with AZD3965 has been shown to increase mitochondrial metabolism and tricarboxylic acid (TCA) cycle-related metabolites, suggesting a shift in how these cells maintain energy balance. However, in cells expressing MCT4, an alternative lactate transporter, resistance to AZD3965 can occur as MCT4 may compensate for MCT1 inhibition.
Clinical Studies and Target Diseases
AZD3965 has progressed into Phase 1 clinical trials for patients with advanced solid tumors and lymphomas. These studies aim to determine the maximum safe dose, identify side effects, and understand how the drug behaves in the body. The trial assesses its safety profile and preliminary efficacy in various cancer types.
The drug is being investigated for a range of cancers, including non-small cell lung cancer, pancreatic cancer, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma. Early findings indicate AZD3965 is well-tolerated, with common side effects being mild to moderate nausea and fatigue. Reversible and asymptomatic retinal changes have been observed, primarily at higher doses, considered on-target effects.
In preclinical models, AZD3965 has demonstrated activity, particularly in lymphoma cell lines with high MCT1 and low MCT4 expression. Studies in mice with small cell lung cancer (SCLC) xenografts have shown AZD3965 can reduce tumor growth and increase intratumor lactate levels. AZD3965 may enhance the effectiveness of other standard cancer treatments, such as doxorubicin and rituximab, used in DLBCL and Burkitt lymphoma.
The Future of AZD3965
The development of AZD3965 holds promise for future cancer treatments, particularly for tumors that rely heavily on MCT1 for metabolism. As a first-in-class MCT1 inhibitor, its progression could establish a new therapeutic strategy. Future clinical trial phases, likely Phase 2, will evaluate its efficacy in specific cancer types susceptible to MCT1 inhibition. These studies will also focus on identifying biomarkers that predict which patients are most likely to respond.
Research is also exploring combination therapies, where AZD3965 could be used alongside existing treatments or other agents that target tumor cell metabolism. The aim is to enhance its anti-tumor effects and overcome resistance mechanisms, such as MCT4 upregulation in some cancer cells. The journey from an investigational drug to a widely available treatment is lengthy, involving several years of rigorous clinical trials and regulatory review. AZD3965’s unique mechanism offers a compelling new direction for cancer therapy.