AI Article Synopsis
- Chk1 is a kinase involved in regulating the cell cycle and responding to DNA damage, particularly at the G(2)/M checkpoint.
- UCN-01, a potent inhibitor of Chk1 currently being tested in clinical trials, disrupts the G(2)/M checkpoint that is activated by DNA damage.
- The crystal structures of Chk1 with UCN-01, staurosporine, and SB-218078 reveal how these compounds bind in the ATP-binding pocket, with UCN-01's unique interactions explaining its selectivity for Chk1 over other kinases.
Article Abstract
Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1074/jbc.M201233200 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Selective inhibition of DNA ligase IV provides additional efficacy to the treatment of anaplastic thyroid cancer.
Front Oncol
February 2024
Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège, Liège, Belgium.
Background: Although the incidence of anaplastic thyroid carcinoma (ATC) is low (2.5% of thyroid cancer cases), this cancer has a very poor prognosis (survival rates < 5 months) and accounts for 14-39% of deaths. Conventional therapies based on surgery in combination with radiotherapy or chemotherapy showed limited effectiveness primarily due to the robust and protective DNA damage response in thyroid cancer cells.
View Article and Find Full Text PDFMyt1 overexpression mediates resistance to cell cycle and DNA damage checkpoint kinase inhibitors.
Front Cell Dev Biol
November 2023
Department of Oncology, University of Alberta, Edmonton, AB, Canada.
Cell cycle checkpoint kinases serve as important therapeutic targets for various cancers. When they are inhibited by small molecules, checkpoint abrogation can induce cell death or further sensitize cancer cells to other genotoxic therapies. Particularly aberrant Cdk1 activation at the G2/M checkpoint by kinase inhibitors causing unscheduled mitotic entry and mitotic arrest was found to lead to DNA damage and cell death selectively in cancer cells.
View Article and Find Full Text PDFThe p38/MK2 Pathway Functions as Chk1-Backup Downstream of ATM/ATR in G-Checkpoint Activation in Cells Exposed to Ionizing Radiation.
Cells
May 2023
Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
We have recently reported that in G-phase cells (but not S-phase cells) sustaining low loads of DNA double-strand break (DSBs), ATM and ATR regulate the G-checkpoint epistatically, with ATR at the output-node, interfacing with the cell cycle through Chk1. However, although inhibition of ATR nearly completely abrogated the checkpoint, inhibition of Chk1 using UCN-01 generated only partial responses. This suggested that additional kinases downstream of ATR were involved in the transmission of the signal to the cell cycle engine.
View Article and Find Full Text PDFThe impairment of DDR reduces XBP1s, further increasing DNA damage, and triggers autophagy via PERK/eIF2alpha in MM and IRE1alpha/JNK1/2 in PEL cells.
Biochem Biophys Res Commun
July 2022
Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy; Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy. Electronic address:
Cancer cells, particularly MM, that are highly secretory cells, and PEL cells that harbor KSHV, are characterized by high level of stress to which they adapt by activating DDR, UPR and autophagy. It is known that UPR sensors may affect DDR, but whether DDR manipulation influences UPR is less known. In this study, we found an intricate interplay between these responses.
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 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!