title: 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.
authors.affiliation: Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA. chenzecheng@hotmail.com
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Dos Santos
authors.forename: Efren
authors.initials: E
authors.lastname: Delos Santos
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Geng
authors.forename: Kim T
authors.initials: KT
authors.lastname: Arndt
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011799:Quinazolines; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin