2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer

Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 08/2009; 19(17):4980-3. DOI: 10.1016/j.bmcl.2009.07.070
Source: PubMed


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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    • "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). "
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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.
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