First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy

2022 ◽  
Author(s):  
Charlotte Dahlem ◽  
Ali Abuhaliema ◽  
Sonja M. Kessler ◽  
Tarek Kröhler ◽  
Ben G. E. Zoller ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Small Molecule ◽  
Rna Binding ◽  
Small Molecule Inhibitors ◽  
Binding Protein ◽  
Rna Binding Protein

Abstract 1133: Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1

2017 ◽  
Author(s):  
Lan Lan ◽  
Amber Smith ◽  
Xiaoqing Wu ◽  
Anuradha Roy ◽  
Ragul Gowthaman ◽  
...  
Keyword(s):  
Small Molecule ◽  
Rna Binding ◽  
Small Molecule Inhibitors ◽  
Binding Protein ◽  
Rna Binding Protein

scholarly journals Targeting the Oncogenic Functions of an RNA-Binding Protein Involved in Hematologic Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2226-2226
Author(s):  
Sean M Post ◽  
Prerna Malaney ◽  
Lauren Chan ◽  
Xiaorui Zhang ◽  
Todd Link ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Intervention ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
B Cell Lymphoma ◽  
Direct Inhibition ◽  
Hnrnp K ◽  
Thermal Shift

Abstract hnRNP K (heterogeneous ribonucleoprotein K) is an RNA-binding protein that binds to conserved poly-C rich tracks in RNA and influences a diverse set of molecular pathways involved in tumorigenesis. Our previous studies identified hnRNP K overexpression in patients with diffuse large B-cell lymphoma (46/75, 61%) and acute myeloid leukemia (45/160, 28%). This overexpression correlates with dismal clinical outcomes and a lack of therapeutic responses to standard treatment. To explore hnRNP K's in vivo functions, we generated Hnrnpk-transgenic mouse models. These mice develop lymphoma phenotypes through activation of the c-Myc pathway. In pre-clinical settings, bromodomain inhibitors disrupted hnRNP K-mediated c-Myc activation, demonstrating that hnRNP K overexpression mediated-pathways are amenable to therapeutic intervention. To further our studies, we used IP-mass spectrometry, RNA-sequencing, RNA immunoprecipitation, reverse phase protein analyses, and polysome profiling to identify novel pathways associated with changes in hnRNP K expression. Here, we observed that alterations in hnRNP K expression result in an impairment of ribosomal biogenesis and activation of pathways directly responsible for global translation. Using both knockdown and overexpression systems, we observed a direct correlation between hnRNP K expression and expression of S6, S6K, phosphorylated S6, eIF and mTOR pathways and uncovered defects in rRNA splicing. Collectively, these data indicate that impairment of cap-dependent loading and alterations in ribogenesis may be a driving force in the clinical manifestations of hnRNP K-driven malignancies. Furthermore, these results suggest that translational-inhibitors may be useful in exploiting hnRNP K-dependent vulnerabilities. To examine this aspect, we are currently using FDA-approved translation inhibitors and disruptors of ribogenesis (e.g. homoharringtonineand mTOR-inhibitors) and KTP- compounds, respectively. While these indirect targeting strategies are interesting, our results indicate that hnRNP K also regulates cellular programs outside of translation. Thus, potential therapies that effectively target hnRNP K overexpression will require direct inhibition of its RNA binding functions. To this end, we used several screening assays including fluorescence anisotropy (FA), surface plasmon resonance, SYPRO-orange thermal shift assays, and cell proliferation assays to screen 80,000 small molecule compounds which led to the identification of 9 candidates that disrupt hnRNP K-mRNA interactions and cause cell death in an hnRNP K-dependent manner. Further, cellular thermal shift assays revealed these lead compounds engage hnRNP K within cells and most critically, result in reduced expression of hnRNP K targets in vivo. These candidate compounds as well as potentially more potent structural analogs are currently being evaluated. Collectively, our results demonstrate that the oncogenic functions of hnRNP K are amenable to both indirect therapeutic intervention using FDA-approved agents as well as direct inhibition through newly identified small molecule compounds, signifying that there may be a roadmap to effective therapies for hnRNP K-dependent malignancies. Disclosures No relevant conflicts of interest to declare.

Discovery of the First Small Molecules Targeting the RNA Binding Protein IGF2BP2/IMP2 as Potential Target in Cancer Therapy

2020 ◽  
Author(s):  
Ali Abuhaliema ◽  
Sonja M. Kessler ◽  
Charlotte Dahlem ◽  
Tarek Kröhler ◽  
Ben G. E. Zoller ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Small Molecules ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Potential Target

Abstract 4817: Molecular cancer therapy targeting RNA-binding protein Musashi-1

2016 ◽  
Author(s):  
Lan Lan ◽  
Hao Liu ◽  
Amber Smith ◽  
Carl Appelman ◽  
Jia Yu ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein

235: The RNA-Binding Protein IMP3: A Novel Molecular Marker Predicts Progression of Superficial (TA and T1) Urothelial Carcinomas of Bladder

2007 ◽  
Vol 177 (4S) ◽  
pp. 78-79
Author(s):  
Lioudmila Sitnikova ◽  
Gary Mendese ◽  
Qin Lui ◽  
Bruce A. Woda ◽  
Di Lu ◽  
...  
Keyword(s):  
Molecular Marker ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Urothelial Carcinomas
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