Drug Development for Chronic Myeloid Leukemia

The emergence of tyrosine kinase inhibitors (TKIs) resistance has necessitated the exploration of new drugs and alternative treatment regimens to minimize disease relapse and enhance overall survival rates. Alfa Cytology is committed to the development of BCR-ABL kinase inhibitors and provides comprehensive drug development services for potential therapies targeting chronic granulocytic leukemia (CML). Our drug development services encompass both BCR-ABL-targeted and non-BCR-ABL-targeted drugs, offering effective alternatives for patients who have developed resistance or intolerance to existing treatments. By focusing on the development of innovative therapies, we strive to overcome the challenges posed by drug resistance and provide viable treatment options for CML.

Introduction of Treatment for Chronic Myeloid Leukemia

The introduction of TKIs has revolutionized the treatment landscape for CML, becoming the standard of care. CML is characterized by a chromosomal translocation between chromosomes 9 and 22, resulting in the formation of the oncogenic fusion gene BCR-ABL1 on chromosome 22. Targeting the BCR-ABL1 kinase is therefore crucial for CML treatment. Researchers have successfully developed TKIs that specifically target the BCR-ABL1 kinase. With the approval of third-generation TKI, ponatinib, the majority of CML patients have achieved long-term remission and are approaching a normal life expectancy.

Fig. 1. Most approved drugs recognize the binding site for ATP in BCR-ABL. (Andretta, E. et al., 2021)

Our Services

For the development of drugs targeting chronic myeloid leukemia (CML), we offer two available options. The first option focuses on the development of novel BCR-ABL1-targeted inhibitors, specifically designed to address TKI resistance in CML. The second option involves the development of therapies targeting non-BCR-ABL1 pathways in CML. By addressing non-BCR-ABL1-mediated resistance in CML leukemia stem cells, these therapies aim to address resistance mechanisms that are independent of the BCR-ABL1 fusion gene.

Development of BCR-ABL Inhibitor for CML

In the development of BCR-ABL inhibitors, we primarily focus on targeting the ATP binding pocket in the kinase domain and the myristoyl pocket. These two regions are key drug targets that we consider in our drug development process. By leveraging these targets, we employ drug design and screening techniques to identify and develop inhibitors that exhibit high specificity and minimal side effects. Our goal is to create inhibitors that can effectively overcome drug resistance commonly observed in BCR-ABL-related diseases.

Development of Non-BCR-ABL Targeted Drugs for CML

Drugs	Service Details
mTOR Inhibitors	We conduct screening of drug candidates that target serine/threonine kinases to inhibit the constitutive activation of mTOR (mammalian target of rapamycin). Subsequently, these candidates underwent rigorous experiments to evaluate their safety and efficacy in the treatment of CML.
JAK/STAT Inhibitors	We employ molecular docking software to facilitate the design and development of drugs that inhibit the enzyme in a metastable manner. Our focus lies on targeting either the kinase structural domain or the pseudokinase structural domain of JAK.
Wnt/β-catenin Inhibitors	By leveraging high-throughput screening (HTS) techniques and exploring the structure-activity relationship, we develop Wnt/β-catenin inhibitors. These inhibitors effectively target and inhibit the activity of β-catenin, thereby impeding the development and maintenance of leukemia stem cells in CML.
Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) Agonists	We conduct a screening of potent inhibitors utilizing Thiazolidinediones as a basis, and we further optimized their structures. Our rigorous experiments enabled us to evaluate the effectiveness of these inhibitors against CML leukemia stem cells.

Development of Antioxidants for CML

Our development efforts focus on antioxidants to mitigate oxidative stress and inhibit the emergence of new BCR-ABL mutations, thereby exploring the potential application of antioxidants in CML.

Development of Combination Therapy for CML

We offer development services for combination therapies involving TKIs and other drugs, such as interferon-α, chemotherapeutic agents, and immunomodulators. Through dosage testing and adjustment of the drug combination regimen, we assess their potential additive or synergistic effects in treating CML. This allows us to evaluate the combined therapeutic efficacy and optimize treatment outcomes.

Advantages of Our Services

With a comprehensive understanding of the pathophysiology and molecular mechanisms of CML, we provide the best solutions for each project.
In addition to BCR-ABL1 kinase-targeted drug development, we also focus on other molecular targets associated with CML.
We possess advanced high-throughput screening platforms that enable rapid and accurate screening of candidate compounds for treatment of CML.

Whether it's the search for novel BCR-ABL1 inhibitors, inhibition of resistance mechanisms, or drug development targeting other CML-specific targets, Alfa Cytology is dedicated to providing the best drug development solutions. Our goal is to improve the quality of life for CML patients and provide them with better chances of long-term survival through innovative drug development. Contact us to discuss your specific research needs and discover how our services can support your leukemia research endeavors.

Reference

Andretta, E.; et al. Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy. Frontiers in oncology. 2021, 11: 801779.

For research use only. Not intended for any clinical use.