sgi-1776 and Leukemia--Myeloid--Acute

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

Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.

Topics: Amides; Animals; Cell Line, Tumor; Halogenation; Humans; Leukemia, Myeloid, Acute; Mice; Models, Molecular; Picolinic Acids; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-pim-1

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cytarabine; Drug Synergism; Humans; Imidazoles; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1; Pyridazines

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Evaluation, Preclinical; fms-Like Tyrosine Kinase 3; Gene Duplication; Humans; Imidazoles; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutant Proteins; Mutation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Proto-Oncogene Proteins c-pim-1; Pyridazines; Substrate Specificity; Tandem Repeat Sequences

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.

Topics: Animals; Apoptosis; Cell Line, Tumor; Enzyme Inhibitors; Female; Gene Expression; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-pim-1; Pyridazines; Xenograft Model Antitumor Assays