Breaking into Merck's CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics
Journal Title: Drug Designing & Intellectual Properties International Journal - Year 2018, Vol 1, Issue 2
Abstract
Early anti-cancer research was dominated by the development of alkylating agents, followed by the discovery of a variety of anti-metabolites, which were useful anti-viral agents at the same time. Current anti-cancer drugs are designed towards molecular targets in order to reduce their toxicity and to enhance the selectivity on the cancer cells. Within an increasingly growing number of molecular targets, the cholecystokinin, as a neuro modulator, became an important anti-cancer target, especially when it was shown that cholecystokinin regulates the invasiveness of human pancreatic cancer cell lines via the protein kinase C pathway. The low potency and the lack of subtype receptor selectivity of those early non-peptide CCK-antagonists, was improved in the following generations of CCK antagonists. These potent and selective antagonists have shown disappointing results in clinical trials due to a poor bioavailability. Initially cholecystokinin was discussed as growth factor, not only in pancreatic cancer, but also for lung, breast, colon and brain cancer, followed by a detailed discussion of over 20 different chemical classes having been developed to date, mainly for the area of neuroscience. Loxiglumide, CI-988, Devazepide, L-365,260 and YM022 are highlighted including in vivo studies and clinical trials. Moreover, CCK antagonists were found useful in the enhancement of the analgesic effects of morphine and the anti-neo plastic effect of cis-platinium. Clinical trials are ongoing. It is concluded that non peptidal cholecystokinin receptor antagonists are modern, non-toxic anti-cancer agents. Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neo plastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. Studies have shown that these GI hormones may play an inhibitory role in the development of pancreatic cancer. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from non-invasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.
Authors and Affiliations
Eric Lattmann, Pornthip Lattmann
Keywords
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- EP ID EP585736
- DOI 10.32474/DDIPIJ.2018.01.000106
- Views 191
- Downloads 0
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