A5046446570- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- RNA and protein synthesis mechanisms
- Acute Myeloid Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Protein Structure and Dynamics
- Bone Tumor Diagnosis and Treatments
- Click Chemistry and Applications
- RNA Research and Splicing
- Sarcoma Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- Glycosylation and Glycoproteins Research
- Cancer-related gene regulation
- Protease and Inhibitor Mechanisms
- Chemical Synthesis and Analysis
- 14-3-3 protein interactions
- Microbial metabolism and enzyme function
- Ziziphus Jujuba Studies and Applications
- Enzyme Structure and Function
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Protein Tyrosine Phosphatases
- S100 Proteins and Annexins
- T-cell and B-cell Immunology
University of Michigan
2016-2024
Yale University
2020-2024
Gladstone Institutes
2014
The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or mutations nucleophosmin (NPM1) gene. As step toward clinical translation menin-MLL1 inhibitors, we report development MI-3454, highly potent orally bioavailable inhibitor interaction. MI-3454 profoundly inhibited proliferation induced differentiation cells primary patient samples NPM1 mutations. When applied as single agent,...
Significance The ability to organize biological molecules into new hierarchical forms represents an important goal in synthetic biology. However, designing quaternary interactions between protein subunits has proved technically challenging and generally required extensive redesign of protein−protein interfaces. Here, we demonstrate a conceptually simple way assemble well-defined geometric structure that uses coiled-coil sequences as “off-the-shelf” components. This approach is inherently...
The protein-protein interaction between menin and mixed-lineage leukemia 1 (MLL1) plays an important role in development of acute with translocations the MLL1 gene solid tumors. Here, we report a new generation menin-MLL1 inhibitors identified by structure-based optimization thienopyrimidine class compounds. This work resulted compound 28 (MI-1481), which showed very potent inhibition (IC50 = 3.6 nM), representing most reversible inhibitor reported to date. crystal structure menin-28 complex...
Type I melanoma antigen (MAGE) family members are detected in numerous tumor types, and expression is correlated with poor prognosis, high grade, increased metastasis. MAGE proteins typically restricted to reproductive tissues, but can recur during tumorigenesis. Several biochemical functions have been elucidated for them, notably, MAGEs regulate proteostasis by serving as substrate recognition modules E3 ligase complexes. The repertoire of complexes that be hijacked targeted protein...
Protein–protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors BCL6BTB has remained challenging. Using NMR-based screening library fragment-like small molecules, we identified thiourea compound (7CC5) that binds to BCL6BTB. From this hit, application computer-aided drug design (CADD), medicinal...
A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and coactivators. Seemingly incongruent with tight regulation transcription, many biochemical biophysical studies suggest that use nonspecific hydrophobic and/or electrostatic interactions to bind coactivators, few if any specific contacts. Here a mechanistic dissection set representative activator•coactivator complexes, comprised ETV/PEA3...
GAS41 is a chromatin-associated protein that belongs to the YEATS family and involved in recognition of acetyl-lysine histone proteins. A unique feature presence C-terminal coiled-coil domain, which responsible for dimerization. Here, we characterized specificity domain found it preferentially binds acetylated H3K18 H3K27 peptides. Interestingly, full-length, dimeric diacetylated H3 peptides with an enhanced affinity when compared those monoacetylated peptides, through bivalent binding mode....
Transcriptional coactivators are a molecular recognition marvel because single domain within these proteins, the activator binding or ABD, interacts with multiple compositionally diverse transcriptional activators. Also remarkable is structural diversity among ABDs, which range from conformationally dynamic helical motifs to those stable core such as β-barrel. A significant objective define conserved properties of ABDs that allow them interact disparate sequences. The ABD coactivator Med25...
Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in cells has demonstrated therapeutic potential, however, as a it classically deemed "undruggable". Given that direct pharmacological intervention against proven difficult, attempts at have instead targeted upstream kinases. Recently, afatinib, FDA-approved kinase inhibitor, been shown to modulate levels multiple cell lines. Herein, we use afatinib lead undertake...
Abstract Patients with MLL-rearranged leukemia typically have a poor prognosis. With chemotherapy and stem cell transplantation as current standard of care, the 5-year survival rate is estimated to be only about 35%. As leukemogenic activity MLL fusion proteins has been shown dependent on their direct interaction menin, development small molecules that block menin-MLL promising therapeutic strategy for treatment this disease. Although molecule inhibitors reported, previously published...
Abstract Efficient determination of protein ligandability, or the propensity to bind small-molecules, would greatly facilitate drug development for novel targets. Ligandability is currently assessed using computational methods that typically consider static structural properties putative binding sites by experimental fragment screening. Here, we evaluate ligandability conserved BTB domains from cancer-relevant proteins LRF, KAISO, and MIZ1. Using screening, discover MIZ1 binds multiple...
Abstract A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and coactivators. Seemingly incongruent with tight regulation transcription, many biochemical biophysical studies suggest that use nonspecific hydrophobic and/or electrostatic interactions to bind coactivators, few if any specific contacts. Here a mechanistic dissection set representative activator•coactivator complexes, comprised...
Abstract Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in cells has demonstrated therapeutic potential, however, as a it classically deemed “undruggable”. Given that direct pharmacological intervention against proven difficult, attempts at have instead targeted upstream kinases. Recently, afatinib, FDA‐approved kinase inhibitor, been shown to modulate levels multiple cell lines. Herein, we use afatinib lead...
Abstract Background: Glioma amplified sequence 41 (GAS41) belongs to the Yaf9, ENL, AF9, Taf14, and Sas5 (YEATS) domain family of epigenetic reader proteins. This preferentially recognizes acetylated lysine residues on chromatin facilitate gene expression by recruiting remodeling transcription activating complexes. The YEATS4 encoding for GAS41 protein is frequently in NSCLC patient samples relative normal lung tissue, overexpressed cells. In knockdown experiments using xenograft mouse...
Edition is aj ournalo ft he Gesellschaft Deutscher Chemiker (GDCh), the largest chemistryrelated scientific society in continental Europe.Information on various activities and services of GDCh, for example, cheaper subscription to Angewandte Chemie International Edition,aswell as applications membership can be found at www.gdch.deor requested from Postfach 900440, D-60444 Frankfurt am Main, Germany.…determines product selectivity oxidative coupling CH 4 shown cover.In their Communication...