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Fadraciclib: A New Drug for Cancer Treatment

What is Fadraciclib?


Fadraciclib (CYC065) is an orally and intravenously available inhibitor of two cancer-driving proteins from the cyclin-dependent kinase family that has been implicated in the pathogenesis of multiple types of cancer: CDK2 and CDK9. It was recently discovered by scientists at The Institute of Cancer Research in London and the company "Cyclacel." The CEO of Cyclacel Pharmaceuticals explained that the main objective of the collaboration between the organizations was to discover, develop, and characterize novel and improved active CDK inhibitors compared to earlier generations of this medicine.

How Fadraciclib works and the potential it holds


Fadraciclib was designed by improving some chemical properties of seliciclib, a previous CDK inhibitor. Researchers have provided evident data that shows CDK2 and CDK9 being inhibited in cancer cells treated by Fadraciclib, leading to altered gene expression and cancer cells' death by apoptosis. These alterations led to 20 times more activity against CDK2 and CDK9 genes, as well as a 30 times increase in therapeutic potency against several human cancer cells and 256 other protein kinases. (Image on the right is courtesy of Guide to Pharmacology).

Research funded by Cyclacel was able to describe experiments in cells and mice and cells that display the potential Fadraciclib has in treating leukemia. It inhibited the growth of human acute myeloid leukemia tumors in mice. Furthermore, scientists have observed that cancer cells treated with Fadraciclib had a sustained decrease in the levels of MCL1, a protein that assists cancer cells in their survival and drug resistance.


Early-stage clinical trials and results


Fadraciclib is currently involved in early Phase 1 clinical trials. In the first trial, the drug is used as a single agent in patients with advanced tumors; in the second, it is used in combination with the approved BCL2 inhibitor in relapsed refractory chronic lymphocytic leukemia patients; lastly, it is combined with Venetoclax to treat relapsed refractory acute myeloid leukemia or myelodysplastic syndrome.


Experimental results show Fadraciclib’s anti-cancer activity through CDK2 and CDK9 inhibition. In breast cancer studies, short-pulse Fadraciclib treatment demonstrated advantageous activity against changed cells over normal cells. This result supports the potential benefit in treating cancers addicted to cyclin E proteins associated with CDK2. The drug activates kinase activity shortly before cells enter into the synthesis phase, which can be targeted by CDK2 inhibition.


Scientists observed Fadraciclib inhibiting CDK9 and suppressing the MCL1 protein, which induced apoptosis for leukemia cells. The drug also demonstrated cooperation with BCL2 inhibitors, such as Venetoclax in acute myeloid leukemia cells. In mouse xenograft models of acute myeloid leukemia and mixed lineage leukemia, researchers have observed that nearly 100% of tumor growth was inhibited by oral administration of Fadraciclib.


Conclusion


Millions of people worldwide are diagnosed with cancer every year, and more than half of the patients die from it. It is a major emotional burden not only for the patient but also for their family and friends. Cancer ranks as the second most common cause of death globally and is responsible for around 9.6 million deaths in 2018. However, Fadraciclib shows promising results that could hopefully help researchers advance their research and eliminate this disease for good.


References


Cancer. (2018, September 12). Retrieved November 11, 2020, from

https://www.who.int/news-room/fact-sheets/detail/cancer

Cyclacel. (2020, July 13). Cyclacel’s Clinical Stage CDK2/9 Inhibitor Fadraciclib Targets Key

Anti-Apoptotic and Oncogenic Pathways in Cancer. Retrieved November 10, 2020, from

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Cyclacel’s Clinical Stage CDK2/9 Inhibitor Fadraciclib Targets Key Anti-Apoptotic and

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Gautier, L. (2020, July 14). Fadraciclib: A new and improved CDK inhibitor for cancer.

Retrieved November 9, 2020, from https://www.oncology-central.com/fadraciclib-a-new

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Institute of Cancer Research. (2020, July 14). Researchers reveal discovery of new cancer drug

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Featured image is courtesy of Gracia Lam.


Article author: Celine Guirguis

Article editors: Sherilyn Wen, Olivia Ye

Article in French Here