FLT3 Inhibitors Development Services
FTL3 inhibitors are effective targeted small molecular drugs for the treatment of acute myeloid leukemia (AML). Alfa Cytology specializes in preclinical FLT3 inhibitor development services to advance targeted therapies for Acute Myeloid Leukemia (AML). FLT3 mutations drive leukemogenesis in approximately 30% of AML patients, making FLT3 a critical therapeutic target. Our customized experimental designs integrate your specific research objectives, compound mechanisms, and therapeutic goals, employing disease-relevant models to accelerate the development of clinically effective FLT3-targeted therapies.
Introduction to FLT3
FLT3 is a class III receptor tyrosine kinase (RTK) transmembrane receptor constitutively expressed in hematopoietic progenitor cells. Its activation by FLT3 ligand (FLT3L) triggers downstream signaling cascades that regulate essential hematopoietic functions, including stem cell proliferation, differentiation, and survival. Oncogenic FLT3 mutations – particularly internal tandem duplications (ITD) and tyrosine kinase domain (TKD) variants – drive constitutive activation of this pathway. This results in uncontrolled leukemic cell proliferation, enhanced cell survival, and apoptosis resistance, directly contributing to AML pathogenesis.
Fig. 1. Chemical structures of reported FLT3 kinase inhibitors. (Dokla, E.M.E. et al., 2022)
Clinically, FLT3 mutations are among the most frequent genetic alterations in AML, occurring in approximately 30% of patients and correlating with poor prognosis. These molecular characteristics establish FLT3 as a high-priority drug target. Recent advances have validated FLT3 inhibitors as a promising therapeutic strategy, with multiple agents demonstrating significant anti-leukemic activity in both preclinical models and clinical trials, leading to FDA-approved therapies for FLT3-mutated AML.
Given the prevalence and poor prognosis of FLT3 mutations in acute myelocytic leukemia, targeting FLT3 signaling with small molecule inhibitors is a therapeutic strategy worthy of investigation.
Design Strategy of FLT3 Inhibitors
The molecular design and drug simulation are carried out using a new generation of molecular modeling and simulation environment tools. According to the compound's action target, the drug's molecular structure was designed. Through the synthesis and testing of structural analogs and derivatives of candidate compounds, the relationship between structure and activity was determined, and the potency and selectivity of drugs were optimized.
Screening Candidate FLT3 Inhibitors
Using our high-throughput screening platform, we screen out effective candidates for FLT3. Each compound in the compound library reacts to the target separately. This is usually achieved through automated equipment and high-throughput screening platforms. The compounds in the compound library are added to the screening experiment one by one, and then the activity of the compound is evaluated by measuring the activity of the target or the interaction with the target.
Deciphering the mechanism of FLT3 Inhibitors
| Experiment | Service Contents |
|---|---|
| Cytostatic assay | The concentration of drugs or inhibitors needed to inhibit 50% of biological processes or reactions was determined by Half-maximal inhibitory concentration (IC50) to evaluate the effective inhibitory activity of drugs against FLT3-ITD mutants. |
| Apoptosis | Apoptosis detection techniques, such as flow cytometry, were used to evaluate whether candidate compounds induce apoptosis in FLT3 mutant leukemic cells. |
| Identification of signaling pathways | The signaling pathways of the effects of candidate compounds on leukemic cells are usually evaluated by the content of key proteins ERK1/2 and mTOR on the signaling pathway and the phosphorylation of downstream signaling factors. |
| Evaluation of drug efficacy | The inhibitory effect of candidate compounds on the growth and spread of leukemic cells is usually evaluated by measuring tumor volume, number of leukemic cells, or survival rate. |
| Drug toxicity analysis | The toxicity of candidate compounds to normal cells and tissues was evaluated using mouse or other leukemia animal models. |
Alfa Cytology provides development services for FLT3 inhibitors, covering drug design, screening, and efficacy research to find ideal drug candidates for you and accelerate preclinical research on your leukemia drugs. These results can guide further drug optimization, reasonable dose selection, and preclinical drug safety evaluation. Contact us if you are interested in our services or would like to know more.
Reference
- Dokla, E.M.E.; et al. Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia. Bioorganic & Medicinal Chemistry. 2022, 56: 116596.