Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition.
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.
Dehnhardt
Christoph M
CM
Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA. dehnhac@wyeth.com
Venkatesan
Aranapakam M
AM
Chen
Zecheng
Z
Ayral-Kaloustian
Semiramis
S
Dos Santos
Osvaldo
O
Delos Santos
Efren
E
Curran
Kevin
K
Follettie
Max T
MT
Diesl
Veronica
V
Lucas
Judy
J
Geng
Yi
Y
Dejoy
Susan Quinn
SQ
Petersen
Rosanne
R
Chaudhary
Inder
I
Brooijmans
Natasja
N
Mansour
Tarek S
TS
Arndt
Kim
K
Chen
Lei
L
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D051820:TCF Transcription Factors / Q000187:drug effects*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D011799:Quinazolines; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin