PDK1 (3-phosphoinositide-dependent protein kinase-1) is a member of the AGC (cAMP-dependent, cGMP-dependent, protein kinase C) family of protein kinases, and has a key role in insulin and growth-factor signalling through phosphorylation and subsequent activation of a number of other AGC kinase family members, such as protein kinase B. The staurosporine derivative UCN-01 (7-hydroxystaurosporine) has been reported to be a potent inhibitor for PDK1, and is currently undergoing clinical trials for the treatment of cancer. Here, we report the crystal structures of staurosporine and UCN-01 in complex with the kinase domain of PDK1. We show that, although staurosporine and UCN-01 interact with the PDK1 active site in an overall similar manner, the UCN-01 7-hydroxy group, which is not present in staurosporine, generates direct and water-mediated hydrogen bonds with active-site residues. Inhibition data from UCN-01 tested against a panel of 29 different kinases show a different pattern of inhibition compared with staurosporine. We discuss how these differences in inhibition could be attributed to specific interactions with the additional 7-hydroxy group, as well as the size of the 7-hydroxy-group-binding pocket. This information could lead to opportunities for structure-based optimization of PDK1 inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1223700 | PMC |
| http://dx.doi.org/10.1042/BJ20031119 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Evaluation of a Pooling Chemoproteomics Strategy with an FDA-Approved Drug Library.
Biochemistry
February 2023
Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Chemoproteomics is a key platform for characterizing the mode of action for compounds, especially for targeted protein degraders such as proteolysis targeting chimeras (PROTACs) and molecular glues. With deep proteome coverage, multiplexed tandem mass tag-mass spectrometry (TMT-MS) can tackle up to 18 samples in a single experiment. Here, we present a pooling strategy for further enhancing the throughput and apply the strategy to an FDA-approved drug library (95 best-in-class compounds).
View Article and Find Full Text PDFComprehensive Bioinformatics Analysis of Toll-Like Receptors (TLRs) in Pan-Cancer.
Biomed Res Int
August 2022
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, 430030 Wuhan, China.
Background: To conduct a comprehensive bioinformatics analysis on the transcriptome signatures of Toll-like receptors (TLRs) in pan-cancer. . A total of 11,057 tissues consisting of 33 types of carcinoma in The Cancer Genome Atlas (TCGA) were retrieved, and then we further explored the correlation between TLRs' expression with tumorigenesis, immune infiltration, and drug sensitivity.
View Article and Find Full Text PDFp53 oligomerization status as an indicator of sensitivity of p53-wildtype neuroblastomas to the combination of DNA damaging agent and Chk1 inhibitor.
PLoS One
March 2022
Department of Biology, University of Hartford, West Hartford, Connecticut, United States of America.
Neuroblastomas are one of the most common types of solid tumors in infants and children and are responsible for approximately 15% of childhood cancer deaths. Neuroblastomas rarely have mutations in p53, with less than 2% of NB containing mutations in p53, compared to up to 60% for other tumor classes. Previous studies on the therapeutic combination of a DNA damaging agent and checkpoint kinase 1 (Chk1) inhibitor have shown that DNA damage-induced cell cycle arrest can be specifically abrogated in p53-defective tumors.
View Article and Find Full Text PDFComputationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation.
Brief Bioinform
January 2022
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design.
View Article and Find Full Text PDFThe structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01.
J Biol Chem
December 2021
School of Chemistry, University of Bristol, Bristol, UK. Electronic address:
The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!