First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer.
Adenocarcinoma
/ drug therapy
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
DNA Damage
DNA Helicases
/ antagonists & inhibitors
DNA-Binding Proteins
/ antagonists & inhibitors
Drug Screening Assays, Antitumor
Enzyme Inhibitors
/ pharmacology
Epithelial-Mesenchymal Transition
/ drug effects
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Knockdown Techniques
High-Throughput Screening Assays
Humans
Kaplan-Meier Estimate
Mice
Neoplasm Proteins
/ antagonists & inhibitors
Organoids
/ drug effects
RNA, Messenger
/ biosynthesis
RNA, Neoplasm
/ biosynthesis
Recombinant Proteins
/ metabolism
Small Molecule Libraries
TCF Transcription Factors
/ physiology
Transcription, Genetic
/ drug effects
Wnt Signaling Pathway
/ drug effects
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
12
02
2020
revised:
03
04
2020
accepted:
21
05
2020
pubmed:
6
6
2020
medline:
27
5
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target. We sought to characterize the clinicopathologic link between CHD1L and colorectal cancer, determine the mechanism(s) by which CHD1L drives malignant colorectal cancer, and discover the first inhibitors with potential for novel treatments for colorectal cancer. The clinicopathologic characteristics associated with CHD1L expression were evaluated using microarray data from 585 patients with colorectal cancer. Further analysis of microarray data indicated that CHD1L may function through the Wnt/TCF pathway. Thus, we conducted knockdown and overexpression studies with CHD1L to determine its role in Wnt/TCF-driven epithelial-to-mesenchymal transition (EMT). We performed high-throughput screening (HTS) to identify the first CHD1L inhibitors. The mechanism of action, antitumor efficacy, and drug-like properties of lead CHD1L inhibitors were determined using biochemical assays, cell models, tumor organoids, patient-derived tumor organoids, and
Identifiants
pubmed: 32499299
pii: 1535-7163.MCT-20-0106
doi: 10.1158/1535-7163.MCT-20-0106
pmc: PMC7665848
mid: NIHMS1599027
doi:
Substances chimiques
Antineoplastic Agents
0
DNA-Binding Proteins
0
Enzyme Inhibitors
0
Neoplasm Proteins
0
RNA, Messenger
0
RNA, Neoplasm
0
Recombinant Proteins
0
Small Molecule Libraries
0
TCF Transcription Factors
0
DNA Helicases
EC 3.6.4.-
CHD1L protein, human
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1598-1612Subventions
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251361
Pays : United States
Organisme : Department of Defense
ID : W81XWH-18-1-0142
Pays : International
Informations de copyright
©2020 American Association for Cancer Research.
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