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

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. Analog...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901370m