Identification and Validation of Small Molecule Inhibitors Targeting FGFR through Molecular Docking-Based Screening
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1113567 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29083969_1.fastq.gz | Fastqsanger.gz | |||
| SRR29083969_2.fastq.gz | Fastqsanger.gz | |||
| SRR29083970_1.fastq.gz | Fastqsanger.gz | |||
| SRR29083970_2.fastq.gz | Fastqsanger.gz | |||
| SRR29083971_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Fibroblast growth factors and their receptors (FGFRs) play important roles in multiple cellular processes. FGFR genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in various cancer types, contributing to the initiation and progression of tumors by enhancing FGFR signaling. Identifying effective small molecule inhibitors that selectively target FGFR can advance cancers therapy driven by FGFR abnormalities. Here, we conducted molecular docking and dynamics simulations to discover new small compounds targeting FGFRs. By docking with 2.8 million small molecules, we identified three promising FGFR inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of these three compounds, we found that ZINC000101867325 formed the most stable binding interactions with FGFRs. After treatment with ZINC000101867325, colorectal cancer cell lines showed a decrease in FGFR phosphorylation and early apoptosis. In addition, ZINC000101867325 is also predicted to interact with FGFR2 mutations in colorectal cancer (CRC) patients. This study provides the novel FGFR inhibitors, and enriches treatment strategies for cancers.
2024-06-30 | GSE267868 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE181471 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168026 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168024 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168023 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168022 | GEO
Project description:Recently, FGFR1 has been found to be overexpressed in osteosarcoma and thus represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity labelling of FGFR1 in an osteosarcoma cell line to identify determinants of FGFR1 activity. Many known FGFR interactors were identified (e.g. FRS2, PLC, RSK2, SHC4, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.
2018-01-29 | PXD006157 | Pride
Project description:Fibroblast growth factors (FGF) play important roles during embryonic development as well as in the adult organism in tissue homeostasis, regeneration, repair and metabolism. We recently showed that inhibition of FGF receptor (FGFR) signaling in keratinocytes either pharmacologically or in a mouse FGFR1/2 knockout model, promoted expression of interferon-stimulated genes (ISGs) (Maddaluno et al, 2020). Here we analyzed the transcriptome of human HaCaT keratinocytes in response to treatment with the FGFR kinase inhibitors AZD4547 and BGJ398.
2024-11-17 | GSE267537 | GEO
Project description:Essential functions of mitogen-activated protein kinases (MAPKs) depend on their capacity to selectively phosphorylate a limited repertoire of substrates. MAPKs harbor a conserved groove located outside of the catalytic cleft that binds to short linear sequence motifs found in substrates and regulators. However, the weak and transient nature of these “docking” interactions poses a challenge to defining MAPK interactomes and associated sequence motifs. Here, we describe a yeast-based genetic screening pipeline to evaluate large collections of MAPK docking sequences in parallel. Using this platform we analyzed a combinatorial library based on the docking sequences from the MAPK kinases MKK6 and MKK7, defining features critical for binding to the stress-activated MAPKs JNK1 and p38α. We subsequently screened a library consisting of ~12,000 sequences from the human proteome, revealing a large number of MAPK-selective interactors, including many not conforming to previously defined docking motifs. Analysis of p38α/JNK1 exchange mutants identified specific docking groove residues mediating selective binding. Finally, we verified that docking sequences identified in the screen could function in substrate recruitment in vitro and in cultured cells. Collectively, these studies establish an approach for characterization of MAPK docking sequences and provide a resource for future investigation of signaling downstream of p38 and JNK MAP kinases.
2022-11-11 | PXD028694 | Pride
Project description:Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded small-molecule library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive computational modeling and biological characterization revealed that BBC1115 binds to BET protein BRD4 and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, and colorectal cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous pancreatic and colorectal cancer xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously employed across normal and malignant cells, it will be critical to evaluate whether BBC1115 interferes with normal cellular functions. Nonetheless, our study implicates that integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies.
2023-02-16 | GSE225342 | GEO