2. Academic Validation
  3. Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition

Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition

  • J Med Chem. 2010 Jan 28;53(2):897-910. doi: 10.1021/jm901370m.
Christoph M Dehnhardt 1,  Aranapakam M Venkatesan,  Zecheng Chen,  Semiramis Ayral-Kaloustian,  Osvaldo Dos Santos,  Efren Delos Santos,  Kevin Curran,  Max T Follettie,  Veronica Diesl,  Judy Lucas,  Yi Geng,  Susan Quinn Dejoy,  Rosanne Petersen,  Inder Chaudhary,  Natasja Brooijmans,  Tarek S Mansour,  Kim Arndt,  Lei Chen
Affiliations

Affiliation

  • 1 Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA. dehnhac@wyeth.com
PMID: 20025292 DOI: 10.1021/jm901370m
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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