ETC-159
Duke-NUS Graduate Medical School; Experimental Therapeutics Centre of Singapore
Cysteine palmitoyltransferase porcupine inhibitor
- By Proffitt Kyle David; Madan Babita; Ke Zhiyuan; Pendharkar Vishal; Ding Lijun; Lee May Ann; Hannoush Rami N; Virshup David M
Cancer research (2013), 73(2), 502-7…..http://cancerres.aacrjournals.org/content/73/2/502.abstract
Ke, Z.; Madan, B.; Lim, S.Q.Y.; et al.
A novel porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations
106th Annu Meet Am Assoc Cancer Res (AACR) (April 18-22, Philadelphia) 2015, Abst 4449
Madan, B.; Ke, Z.; Lim, S.Q.Y.; et al.
Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers
25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst C248
2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
| Abstract Number: | C248 |
| Presentation Title: | Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers |
| Presentation Time: | Tuesday, Oct 22, 2013, 12:30 PM – 3:00 PM |
| Location: | Exhibit Hall C-D |
| Author Block: | Babita Madan1, Zhiyuan Ke2, Shermaine Q.y. Lim2, Jenefer Alam2, Soo Yei Ho2, Duraiswamy A. Jeyaraj2, Kakaly Ghosh1, Yun Shan Chew2, Jamal Aliyev1, Li Jun Ding2, Vishal Pendharkar2, Sifang Wang2, Kanda Sangthongpitag2, Thomas Keller2, May Ann Lee2, David M. Virshup1. 1Duke-NUS Graduate Medical School, Singapore, Singapore; 2Experimental Therapeutics Center, A*STAR, Singapore, Singapore |
| Abstract Body: | Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity |
Abstract C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers.
- Babita Madan1,
- Zhiyuan Ke2,
- Shermaine Q.y. Lim2,
- Jenefer Alam2,
- Soo Yei Ho2,
- Duraiswamy A. Jeyaraj2,
- Kakaly Ghosh1,
- Yun Shan Chew2,
- Jamal Aliyev1,
- Li Jun Ding2,
- Vishal Pendharkar2,
- Sifang Wang2,
- Kanda Sangthongpitag2,
- Thomas Keller2,
- May Ann Lee2, and
- David M. Virshup1
+Author Affiliations
Abstract
Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C248.
Citation Format: Babita Madan, Zhiyuan Ke, Shermaine Q.y. Lim, Jenefer Alam, Soo Yei Ho, Duraiswamy A. Jeyaraj, Kakaly Ghosh, Yun Shan Chew, Jamal Aliyev, Li Jun Ding, Vishal Pendharkar, Sifang Wang, Kanda Sangthongpitag, Thomas Keller, May Ann Lee, David M. Virshup. Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C248.
Made-in-Singapore cancer drug advances to clinical trials on humans
The drug, ETC-159, was developed in a collaboration between A*STAR and Duke-NUS, and is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers.
- POSTED: 16 Jul 2015 10:13
SINGAPORE: A made-in-Singapore cancer drug is touted to be the first publicly-funded drug candidate discovered and developed in Singapore to make it to trials on humans.
In a statement on Thursday (Jul 16), The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS), announced the start of the Phase I clinical trial of novel cancer drug candidate, ETC-159.
The Phase I clinical trial is meant to evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients, and the first patient was dosed on Jun 18. The first two sites for the trial are the National Cancer Centre Singapore and the National University Hospital, and sites in the US will be added as the trial progresses.
The drug is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, which have been identified to promote cancer growth and spread, said the agencies. ETC-159 acts as an inhibitor of these pathways.
“This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies,” said A*STAR and Duke-NUS.
ETC-159 was discovered and developed through a collaboration between A*STAR’s Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. It was based on the discovery work of Prof David Virshup from Duke-NUS.
Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said: “As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients.”
He added: “It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug.”
http://www.channelnewsasia.com/news/singapore/made-in-singapore-cancer/1988090.html?cid=FBSG
Duke-NUS Graduate Medical School, Singapore, Singapore
Experimental Therapeutics Center, A*STAR, Singapore, Singapore
A*STAR Scientist Alex Matter Awarded Prestigious Szent-Gyorgyi Prize For Progress In Cancer
… of the Programme in Cancer and Stem Cell Biology at Duke-NUS, and Professor Alex Matter, chief executive of A*Star’s Experimental Therapeutics Centre
Kanda Sangthongpitag, Ph.D.
Group Leader, Preclinical Pharmacology
Kanda Sangthongpitag obtained a Bachelor of Science (nursing and midwifery) from Mahidol University and worked as the registered nurse in the EENT theatre at the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand. She continued her studies and obtained a Master of Applied Science (Biotechnology) at the University of New South Wales, Sydney, Australia.
May Ann Lee, Ph.D.
Group Leader, Cell Based Assay Development
May Ann Lee completed her PhD in Molecular Biology in Epstein Barr Virus research from State University in New York at Buffalo. Molecular and Cell Biology Department, Roswell Park Cancer Institute in 1993. She did her postdoctoral training in HIV research in the Picower Institute of Medical Research in Manhasset, New York
Experimental Therapeutics Centre (ETC)
31 Biopolis Way
Nanos Level 3
Singapore 138669
Main: +65 6478 8767
Fax: +65 6478 8768
Enquiries: info@etc.a-star.edu.sg
////
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
Join me on Facebook 
Googleplus
amcrasto@gmail.com
LIONEL MY SON
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।
Sorry, the comment form is closed at this time.