Introduction
AZD6738, also known as ceralasertib, is a promising drug candidate developed by AstraZeneca that has been making significant strides in the field of oncology and beyond. This article will delve into the current development status, mechanism of action, clinical trials, and market projections for AZD6738.
Mechanism of Action
AZD6738 is an ATP-competitive, orally bioavailable inhibitor of the Ataxia Telangiectasia and Rad3 related (ATR) serine/threonine protein kinase. ATR plays a crucial role in the DNA damage response (DDR) pathway, making it a key target for cancer therapy. By inhibiting ATR, AZD6738 disrupts cell cycle progression, leads to S-phase accumulation, and increases markers of DNA damage and replication stress, ultimately resulting in cell death, particularly in cells with compromised DNA repair mechanisms[1].
Preclinical Data
Preclinical studies have shown that AZD6738 exhibits potent inhibition of ATR with an in vitro enzyme IC50 of 0.001µM and inhibition of ATR substrate CHK1 Ser345 phosphorylation in cells at an IC50 of 0.074µM. It also demonstrates a good margin of selectivity against other kinases, with no significant inhibition of other PI3K-like kinases such as DNA-PK, ATM, mTOR, or AKT at concentrations up to 1µM[1].
Clinical Trials
Oncology
AZD6738 is currently being evaluated in several clinical trials for its efficacy in treating various types of cancer. A phase II trial is underway to assess the safety, tolerability, and clinical activity of AZD6738 in combination with the checkpoint inhibitor durvalumab in patients with previously treated advanced gastric cancer. This combination aims to enhance cancer immunotherapy by targeting the DDR pathways[2].
Another phase II trial is investigating AZD6738 alone or in combination with olaparib or durvalumab in patients with solid tumors, including renal cell carcinoma, urothelial carcinoma, pancreatic cancer, endometrial cancer, and other advanced solid tumors. This study seeks to determine whether the combination of AZD6738 with these agents can stop the growth of tumor cells more effectively than monotherapies alone[3].
Combination Therapies
AZD6738 has shown synergistic cell killing activity when combined with DNA-damaging chemotherapy agents such as cisplatin, carboplatin, gemcitabine, and bendamustine, or with ionizing radiation. These combinations have demonstrated significant enhancement of anti-tumor activity in xenograft studies, highlighting the potential of AZD6738 as a component of combination therapies in various cancer types[1].
Market Opportunity
The market for ATR inhibitors, including AZD6738, is promising due to their potential in enhancing the effectiveness of DNA-damaging cancer therapies. ATR inhibitors are being explored for use in combination therapies across various cancer types, including ovarian cancer, bile duct carcinoma, breast carcinoma, small cell cancer, and high-grade neuroendocrine cancers, as well as some hematological malignancies[4].
Competitive Landscape
AZD6738 is part of a growing class of ATR inhibitors, which also includes ATG-018, Elimusertib (BAY 1895344), and Camonsertib (RP-3500), developed by other pharmaceutical companies. The competitive landscape suggests a robust market with multiple players, each contributing to the advancement of ATR inhibition in cancer therapy[4].
Potential Beyond Oncology
Interestingly, AZD6738 is also being explored for its potential in preventing type 1 diabetes. Research has shown that AZD6738 can prevent the onset of type 1 diabetes by inducing cell death in self-antigen activated, highly proliferative diabetogenic T cells. This repurposing of AZD6738 highlights its broader therapeutic potential beyond oncology[5].
Market Projections
Given the positive preclinical and clinical data, AZD6738 is poised to make a significant impact in the oncology market. The drug's ability to enhance the efficacy of existing cancer therapies and its potential in combination regimens position it as a valuable asset in the fight against cancer.
Future Outlook
As clinical trials continue to progress, the market is likely to see increased adoption of AZD6738 in various cancer treatment protocols. The drug's oral bioavailability and favorable safety profile further support its potential for widespread use. Additionally, the exploration of AZD6738 in other therapeutic areas, such as type 1 diabetes, could expand its market reach and value.
"ATR inhibitors have shown promise in enhancing the effectiveness of DNA-damaging cancer therapies such as chemotherapy and radiation, making them potential candidates for combination therapies in various cancer types."
- Kuick Research[4]
Key Takeaways
- Mechanism of Action: AZD6738 inhibits the ATR kinase, disrupting DNA damage response pathways and leading to cell death in cancer cells.
- Clinical Trials: Ongoing phase II trials are evaluating AZD6738 in combination with other therapies for various solid tumors and in preventing type 1 diabetes.
- Market Opportunity: The drug has significant potential in the oncology market, particularly in combination therapies, and may also be repurposed for other conditions like type 1 diabetes.
- Competitive Landscape: AZD6738 is part of a growing class of ATR inhibitors, with multiple pharmaceutical companies developing similar compounds.
FAQs
What is AZD6738?
AZD6738, or ceralasertib, is an orally bioavailable inhibitor of the Ataxia Telangiectasia and Rad3 related (ATR) serine/threonine protein kinase, developed by AstraZeneca.
What is the mechanism of action of AZD6738?
AZD6738 inhibits the ATR kinase, which is a key regulator of the DNA damage response pathway, leading to cell cycle disruption and increased markers of DNA damage and replication stress.
In which clinical trials is AZD6738 currently involved?
AZD6738 is being evaluated in phase II trials for its efficacy in treating various solid tumors, including gastric cancer, renal cell carcinoma, urothelial carcinoma, and pancreatic cancer, often in combination with other therapies like durvalumab or olaparib.
What is the market potential of AZD6738?
The market potential of AZD6738 is significant, particularly in the oncology sector, due to its ability to enhance the effectiveness of DNA-damaging cancer therapies and its potential in combination regimens.
Is AZD6738 being explored for uses beyond cancer?
Yes, AZD6738 is also being investigated for its potential in preventing type 1 diabetes by targeting self-antigen activated diabetogenic T cells.
What are the competitive ATR inhibitors in the market?
Other ATR inhibitors include ATG-018, Elimusertib (BAY 1895344), and Camonsertib (RP-3500), developed by companies such as Antengene, Bayer, and Repare Therapeutics.
Sources
- AZD6738 - AstraZeneca Open Innovation. Retrieved from https://openinnovation.astrazeneca.com/preclinical-research/preclinical-molecules/azd6738.html
- Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with previously treated advanced gastric cancer. Retrieved from https://jitc.bmj.com/content/10/7/e005041
- Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Solid Tumors. Retrieved from https://clinicaltrials.ucsf.edu/trial/NCT03682289
- Global ATR Protein Inhibitors Clinical Trials and Market Opportunity. Retrieved from https://www.kuickresearch.com/report-atr-protein-inhibitors-clinical-trials
- An orally available cancer drug AZD6738 prevents type 1 diabetes. Retrieved from https://pubmed.ncbi.nlm.nih.gov/38164129/