Abstract
Background: Rather than a Janus Kinase 2 inhibitor (ruxolitinib), a specific thrombopoietin receptor (TpoR) inhibitor would be more specific for the treatment of myeloproliferative neoplasms due to TpoR mutations.
Objective: A cell-based phenotypic approach to identify specific TpoR inhibitors was implemented and a library of 505,483 small molecules was screened for inhibitory effects on cells transformed by TpoR mutants. Results: Among the identified hits are two analogs of 3-(4-piperidinyl) indole. The analogs showed about five-fold preferential inhibition of cell viability towards Ba/F3 cells expressing the TpoR W515L mutation compared to the parental cells. There was no significant difference in inhibition of cell viability between the TpoR wild type and the TpoR W515L mutant cells. Preferential inhibition of viability was observed in Ba/F3 cells expressing erythropoietin receptor (EpoR) when stimulated with Epo compared to stimulation with interleukin-3 (IL3). The indole analog inhibited ex vivo colony formations of primary bone marrow cells from heterozygous JAK2 V617F knock-in mice. Drug combination treatment study was performed using ruxolitinib and the indole analog. Drug synergistic effects were observed when cells were stimulated to proliferate through both the IL3 and TpoR pathways. Our compound specifically targets monoamine receptors in the rhodopsin-like receptor family of G protein-coupled receptor. Conclusion: This screen has identified a monoamine receptor inhibitor that can inhibit viability of cells with active TpoR or EpoR signalings. Drug synergism with ruxolitib is demonstrated.Keywords: Myeloproliferative neoplasms, thrombopoietin receptor, G protein-coupled receptor, phenotypic screening, drug combination study, Janus Kinase 2.
Combinatorial Chemistry & High Throughput Screening
Title:A Phenotypic Screen for Small-Molecule Inhibitors of Constitutively Active Mutant Thrombopoietin Receptor Implicated in Myeloproliferative Neoplasms
Volume: 19 Issue: 10
Author(s): Anna Ngo, Ann Zhufang Koay, Christian Pecquet, Carmen C. Diaconu, Yasmine Ould-Amer, Qiwei Huang, Congbao Kang, Anders Poulsen, May Ann Lee, David Jenkins, Andrew Shiau, Stefan N. Constantinescu and Meng Ling Choong
Affiliation:
Keywords: Myeloproliferative neoplasms, thrombopoietin receptor, G protein-coupled receptor, phenotypic screening, drug combination study, Janus Kinase 2.
Abstract: Background: Rather than a Janus Kinase 2 inhibitor (ruxolitinib), a specific thrombopoietin receptor (TpoR) inhibitor would be more specific for the treatment of myeloproliferative neoplasms due to TpoR mutations.
Objective: A cell-based phenotypic approach to identify specific TpoR inhibitors was implemented and a library of 505,483 small molecules was screened for inhibitory effects on cells transformed by TpoR mutants. Results: Among the identified hits are two analogs of 3-(4-piperidinyl) indole. The analogs showed about five-fold preferential inhibition of cell viability towards Ba/F3 cells expressing the TpoR W515L mutation compared to the parental cells. There was no significant difference in inhibition of cell viability between the TpoR wild type and the TpoR W515L mutant cells. Preferential inhibition of viability was observed in Ba/F3 cells expressing erythropoietin receptor (EpoR) when stimulated with Epo compared to stimulation with interleukin-3 (IL3). The indole analog inhibited ex vivo colony formations of primary bone marrow cells from heterozygous JAK2 V617F knock-in mice. Drug combination treatment study was performed using ruxolitinib and the indole analog. Drug synergistic effects were observed when cells were stimulated to proliferate through both the IL3 and TpoR pathways. Our compound specifically targets monoamine receptors in the rhodopsin-like receptor family of G protein-coupled receptor. Conclusion: This screen has identified a monoamine receptor inhibitor that can inhibit viability of cells with active TpoR or EpoR signalings. Drug synergism with ruxolitib is demonstrated.Export Options
About this article
Cite this article as:
Ngo Anna, Koay Zhufang Ann, Pecquet Christian, Diaconu C. Carmen, Ould-Amer Yasmine, Huang Qiwei, Kang Congbao, Poulsen Anders, Lee Ann May, Jenkins David, Shiau Andrew, Constantinescu N. Stefan and Choong Ling Meng, A Phenotypic Screen for Small-Molecule Inhibitors of Constitutively Active Mutant Thrombopoietin Receptor Implicated in Myeloproliferative Neoplasms, Combinatorial Chemistry & High Throughput Screening 2016; 19 (10) . https://dx.doi.org/10.2174/1386207319666161010163825
DOI https://dx.doi.org/10.2174/1386207319666161010163825 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Anti-Inflammatory and Antioxidant Properties of Piper Species: A Perspective from Screening to Molecular Mechanisms
Current Topics in Medicinal Chemistry Irreversible Kinase Inhibitors Targeting Cysteine Residues and their Applications in Cancer Therapy
Mini-Reviews in Medicinal Chemistry The Hsp32 Inhibitors SMA-ZnPP and PEG-ZnPP Exert Major Growth-Inhibitory Effects on CD34+/CD38+ and CD34+/CD38- AML Progenitor Cells
Current Cancer Drug Targets Using Simulation in Clinical Education: Psoriasis Area and Severity Index (PASI) Score Assessment
Current Rheumatology Reviews Molecular Imaging with Nucleic Acid Aptamers
Current Medicinal Chemistry Potential Association Between TLR4 and Chitinase 3-Like 1 (CHI3L1/YKL-40) Signaling on Colonic Epithelial Cells in Inflammatory Bowel Disease and Colitis-Associated Cancer
Current Molecular Medicine The Evolving Therapeutic Approaches for Epstein-Barr Virus Infection in Immunocompetent and Immunocompromised Individuals
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Serratia Type Pore Forming Toxins
Current Protein & Peptide Science Pembrolizumab-Induced Seronegative Arthritis and Fasciitis in a Patient with Lung Adenocarcinoma
Current Drug Safety Therapeutic Potential of Natural Compounds in Lung Cancer
Current Medicinal Chemistry Immune Responses to Therapeutic Proteins in Humans - Clinical Significance, Assessment and Prediction
Current Pharmaceutical Biotechnology Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric and Teen Patients Allows Identifying Two Main Classes of Biological Processes Involved and New Potential Therapeutic Targets
Current Genomics Immunotherapy-Based Strategies for the Treatment of Autoimmune Diabetes: Searching for the Cure
Current Pharmaceutical Design Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology
Current Pharmaceutical Design Ceramide and Apoptosis: Exploring the Enigmatic Connections between Sphingolipid Metabolism and Programmed Cell Death
Anti-Cancer Agents in Medicinal Chemistry Clinical Pharmacology of Serotonin Receptor Type 3 (5-HT3) Antagonists
Current Medicinal Chemistry - Central Nervous System Agents Comparative Genomic Hybridization: A Valuable Tool for Genome-Scale Analysis of Rodent Cancer Models
Current Genomics Angiogenesis and Hypoxia in Glioblastoma: A Focus on Cancer Stem Cells
CNS & Neurological Disorders - Drug Targets Inflammation and Antiangiogenesis in Cancer
Current Medicinal Chemistry From Discovery to the Coming Generation of Histone Deacetylase Inhibitors
Current Medicinal Chemistry