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.
"Several strategies have been proposed to block b-catenin protein–protein interactions with small molecules, which are believed to offer a promising route to affect cancer therapy (Dorfman et al. 2003; Arce et al. 2006; Petropoulos et al. 2008; Bengochea et al. 2008; Ravindranath et al. 2008; Nguyen et al. 2009; Chen et al. 2009c; Hale et al. 2009). "
[Show abstract][Hide abstract] 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 axin
TARGETING THE WNT PATHWAY IN CANCER, 01/2011: chapter 9: pages 183-209; Springerlink.
[Show abstract][Hide abstract] 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 molecule
Micromechatronics and Human Science, 1997. Proceedings of the 1997 International Symposium on; 02/1997
[Show abstract][Hide abstract] 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.
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