2,4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer
ABSTRACT The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as beta-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit the beta-catenin/Tcf-4 pathway. Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain as in 2, resulted in a number of new analogues, which are potent inhibitors of the beta-catenin/Tcf-4 pathway. Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability.
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ABSTRACT: Wnt signaling plays important roles in embryonic development and in maintenance of adult tissues. Mutation, loss, or overexpression of key Wnt pathway components has been linked to various types of cancer. Therefore, inhibition of Wnt signaling is of interest for the development of novel anticancer agents. The results of recent structure-based screening, high-throughput screening (HTS), and chemical genomics studies demonstrate that small molecules, including synthetic and natural compounds, can inhibit Wnt signaling in various cancers by blocking specific protein–protein interactions or the activity of specific enzymes. In biological studies, these compounds appear promising as potential anticancer agents; however, their efficacy and toxicity have yet to be investigated. Small molecule inhibitors of Wnt signaling also have wide-ranging potential as tools for elucidating disease and basic biology. Indubitably, in the near future, these compounds will yield agents that are clinically useful against malignant diseases. Abbreviations APC Adenomatous polyposis coli CK1 Casein kinase 1 CLL Chronic lymphocytic leukemia COX Cyclooxygenase CRC Colon carcinoma DEP Dishevelled Egl-10, and pleckstrin DIX Dishevelled and axinTARGETING THE WNT PATHWAY IN CANCER, 01/2011: chapter 9: pages 183-209; Springerlink.
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ABSTRACT: Accurate manipulation of a single DNA molecule will support genome analysis, such as gene mapping, physical mapping and sequencing of chromosome. This paper presents the micromanipulation of single-stranded DNA and its application to gene mapping. As a model template DNA, monomeric λ phage DNA was tandemly ligated which was then denatured and hybridized with a cloned probe DNA of λ-exo gene region. The hybridized molecules were terminally bound with magnetic beads, elongated, and video-imaged. We could observe the islands of gleaming spots which stood in line from a bead at regular intervals. This agree well with the expected images from the construction of the templates and probes. We have also demonstrated the localization of restriction enzyme activity only in a small area of stretched long chromosomal DNA using temperature control technique. The DNAs were digested about 10 μm around the laser focal spot (about 10 pico liter portion) under a microscopic observation view. This technique may open up quick physical mapping by handling a single DNA moleculeMicromechatronics and Human Science, 1997. Proceedings of the 1997 International Symposium on; 02/1997
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ABSTRACT: We are introducing a novel series of 2,4-diaminoquinazolines as beta-catenin/Tcf4 inhibitors which were identified by ligand-based design. Here we elucidate the SAR of this series and explain how we were able to improve key molecular properties such as solubility and cLogP leading to compound 9. Analogue 9 exhibited better biological activity and improved physical and pharmacological properties relative to the HTS hit 49. Furthermore, 9 demonstrated good cell growth inhibition against several human colorectal cancer lines such as LoVo and HT29. In addition, treatment with compound 9 led to gene expression changes that overlapped significantly with the transcriptional profile resulting from the pathway inhibition by siRNA knockdown of beta-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.Journal of Medicinal Chemistry 12/2009; 53(2):897-910. DOI:10.1021/jm901370m · 5.48 Impact Factor