Design and Synthesis of Novel Diaminoquinazolines with in Vivo Efficacy for β-Catenin/T-Cell Transcriptional Factor 4 Pathway Inhibition

• Published in: Journal of medicinal chemistry 2010-01, Vol.53 (2), p.897-910
• Main Authors: Dehnhardt, Christoph M, Venkatesan, Aranapakam M, Chen, Zecheng, Ayral-Kaloustian, Semiramis, Dos Santos, Osvaldo, Delos Santos, Efren, Curran, Kevin, Follettie, Max T, Diesl, Veronica, Lucas, Judy, Geng, Yi, DeJoy, Susan Quinn, Petersen, Rosanne, Chaudhary, Inder, Brooijmans, Natasja, Mansour, Tarek S, Arndt, Kim, Chen, Lei
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - drug effects; beta Catenin - drug effects; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Drug Design; Humans; Mice; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Quinazolines - therapeutic use; Structure-Activity Relationship; TCF Transcription Factors - drug effects; Transcription Factor 4; Transcription Factors - drug effects; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901370m

We are introducing a novel series of 2,4-diaminoquinazolines as β-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 β-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a β-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.