Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors
| Autor: | Thomas H. Keller, Zhiyuan Ke, Vithya Manoharan, May Ann Lee, Anders Poulsen, David M. Virshup, Yun Shan Chew, Kanda Sangthongpitag, Vishal Pendharkar, Soo Yei Ho, Eldwin Sum Wai Tan, Choon Bing Low, Jenefer Alam, Li Jun Ding, Weiling Wang, Babita Madan, Shi Hua Ang, Duraiswamy Athisayamani Jeyaraj, Jeffrey Hill, Grace Lin |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold Cytochrome P-450 CYP1A2 Inhibitors Mice Nude Antineoplastic Agents Scaffold hopping Maleimides Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Cytochrome P-450 CYP2D6 Inhibitors biology.animal Drug Discovery Animals Humans Wnt Signaling Pathway Maleimide Mice Inbred BALB C biology Chemistry Wnt signaling pathway Membrane Proteins Xenograft Model Antitumor Assays In vitro High-Throughput Screening Assays Rats Pyridazines HEK293 Cells 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Microsomes Liver Cytochrome P-450 CYP3A Inhibitors Molecular Medicine Female Pharmacophore Porcupine Acyltransferases |
| Zdroj: | Journal of Medicinal Chemistry. 60:6678-6692 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00662 |
| Popis: | Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported. |
| Databáze: | OpenAIRE |
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