Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.7b01612 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effects of radiotherapy on the hippocampus and hippocampal neurogenesis: a systematic review of preclinical studies.
Strahlenther Onkol
January 2025
Department of Radiation Medicine, Lenox Hill Hospital, Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA.
Purpose: A comprehensive literature review was undertaken to understand the effects and underlying mechanisms of cranial radiotherapy (RT) on the hippocampus and hippocampal neurogenesis as well as to explore protective factors and treatments that might mitigate these effects in preclinical studies.
Methods: PubMed/MEDLINE, Web of Science, and Embase were queried for studies involving the effects of radiation on the hippocampus and hippocampal neurogenesis. Data extraction followed the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines, and a risk of bias assessment was conducted for the included animal studies using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool.
[A Case Report of EGFR-TKIs Resistant Secondary MET Gene Amplified Lung Squamous Cell Carcinoma and Literature Review].
Zhongguo Fei Ai Za Zhi
November 2024
Department of Oncology, The Central Hospital of Shaoyang, Shaoyang 422000, China.
With the rapid development of epidermal growth factor receptor (EGFR) gene testing of lung adenocarcinoma patients has been routinely carried out, EGFR mutations are also possible for some small samples of non-smoking female lung squamous cell carcinoma patients. This increases the opportunity for targeted therapy for this group of patients. However, drug resistance in patients with lung squamous cell carcinoma during targeted therapy is an important factor affecting subsequent treatment.
View Article and Find Full Text PDF[Savolitinib Induced Pathological Complete Response in Non-small Cell Lung Cancer with MET Amplification: A Case Report].
Zhongguo Fei Ai Za Zhi
November 2024
Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300000, China.
Mesenchymal-epithelial transition factor (MET) gene mutation is a large class of mutations commonly seen in non-small cell lung cancer (NSCLC). MET mutation includes subtypes such as MET exon 14 skipping mutation (METex14m) and MET amplification (METamp). For advanced NSCLC with METex14m, Savolitinib has a high sensitivity as a member of tyrosine kinase inhibitors (TKIs).
View Article and Find Full Text PDF[Non-small Cell Lung Cancer Cell Line PC-9 Drug-resistant Mutant Cell Line Establishment and Validation of Their Sensitivity to EGFR Inhibitors].
Zhongguo Fei Ai Za Zhi
November 2024
Yangtze Delta Drug Advanced Research Institute, Nantong 226133, China.
Background: Mutations in the structural domain of the epidermal growth factor receptor (EGFR) kinase represent a critical pathogenetic factor in non-small cell lung cancer (NSCLC). Small-molecule EGFR-tyrosine kinase inhibitors (TKIs) serve as first-line therapeutic agents for the treatment of EGFR-mutated NSCLC. But the resistance mutations of EGFR restrict the clinical application of EGFR-TKIs.
View Article and Find Full Text PDFHDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF-mutant microsatellite stable colorectal cancer.
J Immunother Cancer
January 2025
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
Background: B-Raf proto-oncogene, serine/threonine kinase (BRAF)-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.
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!