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Global Development of CWP232291, a Novel Cancer Drug Targeting Wnt/beta-catenin Signaling_JW_pharmaceutical
Korea Health Industry Development Institute (KHIDI) South Korea flag South Korea
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Global development of CWP232291, a novel cancer drug targeting Wnt/beta-catenin signaling...
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The generation of the acute myelocytic leukemia and treatment


The generation situation of the acute myelocytic leukemia


As to the leukemia onset frequency of the major countries in the world, the ratio which the onset frequency of the acute myelocytic leukemia occupies is 30% or greater. About two times extent generation rate is higher than the chronic myelogenous leukemia, that is the indication of the gleevec.


In the case of the Domestic of a country, 1,541 leukemia patient died in 2008. And, In 2000, showing the increasing rate of 12% in comparison to 1,371 people for as much as 8 years.


The therapeutics of the acute myelocytic leukemia


The primary aim of the leukemia treatment reaches utterly the complete remission.


Presently, there is the Ara-C(Cytarabine), daunorubicin or idarubicin as the cell toxic anti-cancer medicine, much used leukemia treatment drug. However, as to these, even when accompanying the serious side effect, the five-year survival rate of the patients is about 30-40%. Therefore, the necessity of the development of new medicine in which the side effect is small and which increases the survival rate is urgently needed.


In the case of the gleevec, that is the representative drug of the mark anti-cancer drug, it is the drug suppressing the activated kinase activity due to the mutation of the Bcr / Abl protein. Particularly, the effect in the acute myelocytic leukemia, at all, the none there is nearly no effect in the other indication the remarkable anticancer effect is shown in the chronic myelogenous leukemia (CML) patient and basal cell carcinoma (GIST).


Background and unmet needs


Wnt/beta-catenin signaling and pothological physiology of cancer


In the mid 1980's, in the research of the Wnt protein discovered for the first time, it was clarified that over activation of the Wnt signal transmission is very important in the birth of the various cancer, includings the colorectal cancer.


As to the onset of the various cancers, it is reported that abnormal activation of the Wnt signal transduction system is related with and the cyclin D1, cMyc, survivin as Wnt associated gene, and It is reported to play the role of being important in the outbreak of cancer.


Diseases for which medicine is efficacious of cancer drug targeting Wnt/beta-catenin signaling


Wnt/beta-catenin signaling and acute myeloid leukemia


In 61% of the acute myelocytic leukemia patient, over of the Wnt signal transmission and activation were discovered(Leukemia, 2006, 20, 1211).


Wnt/beta-catenin signaling and other cancer


Table 1. The abnormal activation ratio of Wnt/beta-catenin signaling in cancer patient organization



















































































Cancer








Wnt abnormal activation ratio








Assay








Reference








colorectal cancer








80-85%








APC Mutation








Science (1997) 275:1784








acute myelocyte leukemia








61-100%








WB








Leukemia (2006), 20, 1211








lung cancer








75%








WB(Dvl3)








Oncogene (2003)22:7218








stomach[gastric] cancer








40-60%








APC Mutation








(in differentiated types)








liver cancer








78%








Immunohistochemistry








World J Gastr. (2005) 11:2398








pancreatic cancer








39%








Immunohistochemistry








Human Path. (2006), 37:212








prostate cancer








36%








Immunohistochemistry








Int J Can (2005)113:415








cancer of the esophagus








59%








Immunohistochemistry








Int J Can (2005)113:981








breast cancer








13%








WB








EJC (2000) 242:248








multiple myeloma








75-100%








PCR








Ai Zheng (2007) 26:1010








ovarian cancer








27%








Immunohistochemistry








J Path (2004) 204:268



Discovery and Achievements


The the world's first drug CWP232291 (CWP231A), low molecular weight composition anti-cancer drug, blocking Wnt / beta catenin signal transduction path.


The the world's first drug CWP232291 (CWP231A), low molecular weight composition anti-cancer drug, blocking Wnt / beta catenin signal transduction path.



















 




 








Fig2. The core framework of the CWP232291 drug








Fig. 3. The Ara-C and CWP231A (CWP232291) anticancer effect in the leucosis model



Presently, all non-clinical toxicities, pharmacological potency, drugstuff movement (ADME), preparation, and biomarker test about the CWP232291 were successfully completed. And for clinical trial drug production is completed in the overseas GMP CMO.


Pre-IND meeting with US FDA, that was successfully terminated in the early November, 2010. And FDA IND approval in U.S. against the blood cancer patient in October 2011.


The development importance of CWP232291


First-in-Class Wnt targeted anticancer


Table 2. A representative kind of predetermined molecular target anti-cancer drug and indication


 
























































Division








Pharmacophore target








Product








Indication








Signal transduction inhibitor








BCR-ABL








Gleevec








leukemia








HER@








Herceptin








breast cancer








EGFR








Iressa, Erbitux








lung cancer, colorectal cancer








Wnt








nothing








colorectal cancer, leukemia, etc.








Angiogenesis Inhibitor








VEGFR, PDGFR








Avastin, Sutene, Nexavar, Greenstatin, etc.








colorectal cancer, kidney cancer








Immunotherapy








CD20








Rituxan








lymphoma








apoptosis derivative s








26S protase








Velcade








multiple myeloma



The Wnt restraint drugs development current state


Table 3. The Wnt signal transmission suppression anticancer drug development current state
























































 








Target








Development, Inc.








Indication








Note








Antibody drug








Wnt Receptor, Fzd








Genentech








Cancer








acts on the upper signal








Fzd Receptor








OncoMed








Cancer








acts on the upper signal(cooperation research with Bayer)








Low molecular weight drug








β-catenin








JW CHOONGWAE PHARMA CORPORATION








leukemia, multiple myeloma,












lymphoma, colorectal cancer, etc.








acts on the sub-signal








Tcf/β-cat Interaction








novartis, pfizer








Cancer








bad medicamentosa








β-catenin degradation








Avalon








colorectal cancer, multiple myeloma, CML








research initial step








Fzd-Dvl Interaction








Genentech, St. Jude hospital








lung cancer, colorectal cancer








 


FEATURED
Last Updated Jun 2016
Technology Type THERAPEUTIC
Phase of Development EARLY STAGE
GOVERNMENT INSTITUTE