CT100: Harnessing the anti-cancer activity of quercetin
CT100 is a novel and proprietary derivative of quercetin that blocks proliferation through modulating signal transduction, specifically PIM-1 kinase. Celleron has identified biomarkers that have informed on responsive tumours. The product is in Phase I clinical studies, building on clinical observations with quercetin on more than 50 patients
Quercetin is a naturally occurring flavonoid which has been epidemiologically linked to the prevention of cancer; over 500 publications in the literature address the anti-proliferative properties of quercetin. The compound has a range of biochemical properties which are mechanistically related to its anti-cancer properties. Quercetin interacts synergistically with a number of conventional anti-cancer drugs and can sensitise tumour cells and xenografts to cytotoxics like cisplatin, taxol, cytosine arabinoside and doxorubicin. Professor Kerr is a leading expert on quercetin which he studied in a previous clinical Phase I trial and observed clinical activity against ovarian and hepatocellular cancer, and refractory leukaemia.
Although it has been widely assumed that quercetin acts as a general inhibitor of protein kinase activity, recent results acquired by Celleron indicate that quercetin is a specific and high affinity inhibitor of one kinase. The crystal structure of the high affinity interaction between quercetin and Pim1 kinase is shown below. Pim1 kinase is expressed at high levels in certain tumours, such as prostate cancer, and at a general level there is a great deal of interest in developing drugs that target Pim1 kinase. Pim1 phosphorylates substrates that include the BAD protein. Consequently, the expression of Pim1 provides a potential biomarker for responsive tumours, and the phosphorylation level of Pim1 substrates surrogate end points to monitor the inhibition of Pim1 kinase activity in patients.
Regulation of BAD phosphorylation by quercetin.
However, the chemistry of quercetin is not ideal and, as a result, the compound has never progressed into full-blown clinical development. Consequently, a patent protected water soluble chemical derivative of quercetin, CT101, has been designed and studied in a Phase I clinical trial. This Phase I study demonstrated that CT101 is well-tolerated and hydrolyses to release quercetin in patients. The clinical potential of CT101 is very significant and, based on preclinical studies, includes the possibility of single agent activity in prostate, ovarian and hepatocellular cancers. Combination treatments with cisplatin, taxol and their analogues will further open the way forward for a large clinical development programme in lung, prostate, breast and ovarian cancer.
PIM 1 Quercetin Complex (surface representation)
Although it has been widely assumed that quercetin acts as a general inhibitor of protein kinase activity, recent results acquired by Celleron indicate that quercetin is a specific and high affinity inhibitor of one kinase. The crystal structure of the high affinity interaction between quercetin and Pim1 kinase is shown below. Pim1 kinase is expressed at high levels in certain tumours, such as prostate cancer, and at a general level there is a great deal of interest in developing drugs that target Pim1 kinase. Pim1 phosphorylates substrates that include the BAD protein. Consequently, the expression of Pim1 provides a potential biomarker for responsive tumours, and the phosphorylation level of Pim1 substrates surrogate end points to monitor the inhibition of Pim1 kinase activity in patients.
- Regulation of BAD phosphorylation by quercetin.
However, the chemistry of quercetin is not ideal and, as a result, the compound has never progressed into full-blown clinical development. Consequently, a patent protected water soluble chemical derivative of quercetin, CT101, has been designed and studied in a Phase I clinical trial. This Phase I study demonstrated that CT101 is well-tolerated and hydrolyses to release quercetin in patients. The clinical potential of CT101 is very significant and, based on preclinical studies, includes the possibility of single agent activity in prostate, ovarian and hepatocellular cancers. Combination treatments with cisplatin, taxol and their analogues will further open the way forward for a large clinical development programme in lung, prostate, breast and ovarian cancer.
- PIM 1 Quercetin Complex (surface representation)