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Start Over Author "Marcellus R" Journal nature chemical biology
3 results on '"Marcellus R"'

1. A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Author

Saraon P, Snider J, Kalaidzidis Y, Wybenga-Groot LE, Weiss K, Rai A, Radulovich N, Drecun L, Vučković N, Vučetić A, Wong V, Thériault B, Pham NA, Park JH, Datti A, Wang J, Pathmanathan S, Aboualizadeh F, Lyakisheva A, Yao Z, Wang Y, Joseph B, Aman A, Moran MF, Prakesch M, Poda G, Marcellus R, Uehling D, Samaržija M, Jakopović M, Tsao MS, Shepherd FA, Sacher A, Leighl N, Akhmanova A, Al-Awar R, Zerial M, and Stagljar I

Subjects
Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Cell Line, Tumor, DNA Nucleotidyltransferases genetics, Drug Discovery, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Genes, Reporter, Humans, Luciferases genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Mutation, Phosphorylation drug effects, Reproducibility of Results, Small Molecule Libraries pharmacology, Staurosporine analogs & derivatives, Staurosporine pharmacology, High-Throughput Screening Assays methods, Protein Kinase Inhibitors pharmacology
Abstract

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

Published
2020
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3. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.

Author

Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S, Kuznetsova E, Smil D, Barsyte-Lovejoy D, Li F, Poda G, Schapira M, Wu H, Dong A, Senisterra G, Stukalov A, Huber KVM, Schönegger A, Marcellus R, Bilban M, Bock C, Brown PJ, Zuber J, Bennett KL, Al-Awar R, Delwel R, Nerlov C, Arrowsmith CH, and Superti-Furga G

Subjects
Amino Acid Sequence, Animals, CCAAT-Enhancer-Binding Proteins genetics, CCAAT-Enhancer-Binding Proteins metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Histones genetics, Histones metabolism, Humans, Intracellular Signaling Peptides and Proteins, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Molecular Docking Simulation, Molecular Sequence Data, Molecular Targeted Therapy, Mutation, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism, Protein Binding, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Structure, Tertiary, Signal Transduction, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Biphenyl Compounds pharmacology, Dihydropyridines pharmacology, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Leukemia, Myeloid, Acute metabolism, Myeloid-Lymphoid Leukemia Protein antagonists & inhibitors, Small Molecule Libraries pharmacology
Abstract

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

Published
2015
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