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Bioorg Med Chem Lett. 2009 Sep 1;19(17):4980-3. doi: 10.1016/j.bmcl.2009.07.070. Epub 2009 Jul 17.

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

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Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA.


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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