sb-1518 and Leukemia--Myeloid--Acute

Mutations in the FMS-like tyrosine kinase 3 (

Topics: Animals; Drug Discovery; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Models, Molecular; Mutation; Protein Kinase Inhibitors; Small Molecule Libraries

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal growth and differentiation of hematopoietic stem cells. Although the pathogenesis has not been fully elucidated, many specific gene mutations have been found in AML. Fms-like tyrosine kinase 3 (FLT3) is recognized as a drug target for the treatment of AML, and the activation mutations of FLT3 were found in about 30% of AML patients. Targeted inhibition of FLT3 receptor tyrosine kinase has shown promising results in the treatment of FLT3 mutation AML. Unfortunately, the therapeutic effects of FLT3 tyrosine kinase inhibitors used as AML monotherapy are usually accompanied by the high risk of resistance development within a few months after treatment. FLT3 dual inhibitors were generated with the co-inhibition of FLT3 and another target, such as CDK4, JAK2, MEK, Mer, Pim, etc., to solve the problems mentioned above. As a result, the therapeutic effect of the drug is significantly improved, while the toxic and side effects are reduced. Besides, the life quality of AML patients with FLT3 mutation has been effectively improved. In this paper, we reviewed the studies of dual FLT3 inhibitors that have been discovered in recent years for the treatment of AML.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays