A Phenotypic Screen for Small-Molecule Inhibitors of Constitutively Active Mutant Thrombopoietin Receptor Implicated in Myeloproliferative Neoplasms
| Autor: | CongBao Kang, Anders Poulsen, Stefan N. Constantinescu, Andrew K. Shiau, David Jenkins, Meng Ling Choong, Ann Zhufang Koay, May Ann Lee, Anna Ngo, Christian Pecquet, Qiwei Huang, Yasmine Ould-Amer, Carmen C. Diaconu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Phenotypic screening Pharmacology Cell Line Small Molecule Libraries 03 medical and health sciences Bone Marrow Drug Discovery Nitriles Humans Viability assay Receptor G protein-coupled receptor Thrombopoietin receptor Janus kinase 2 Myeloproliferative Disorders biology Organic Chemistry Wild type Drug Synergism General Medicine Molecular biology Computer Science Applications Erythropoietin receptor High-Throughput Screening Assays 030104 developmental biology Pyrimidines Mutation biology.protein Pyrazoles Receptors Thrombopoietin Signal Transduction |
| Zdroj: | Combinatorial chemistryhigh throughput screening. 19(10) |
| ISSN: | 1875-5402 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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