Research & Development
Other Programs
CYC065 – Second Generation CDK Inhibitor
Cyclacel Pharmaceuticals is developing a new generation of CDK inhibitors for application in oncology and other proliferative diseases. CYC065 is the lead compound in a series of derivatives of seliciclib which retain the desirable CDK inhibition profile and mechanism of action of seliciclib, but demonstrate increased anti-proliferative potency and improved pharmaceutical properties. CYC065 has shown potent antitumor activity in xenograft models of haematological and solid tumor malignancies. Pharmacological inhibition of CDK2 and CDK9 has been shown to have potent anticancer effects in certain tumor types resistant to established treatments. Published preclinical studies show that CYC065 and other derivatives have the potential for development in acute myeloid leukemia, chronic lymphocytic leukemia and drug resistant breast cancer. Investigational new drug (IND) enabling studies for CYC065 are underway.
Polo-like Kinase Inhibitors for Oncology
Activity of the mitotic kinase Plk1 is strongly associated with cancer progression. Several studies have shown correlations between elevated Plk1 expression, histological grade and poor prognosis in several types of cancer. Plk1 may have a role in oncogenesis through its regulation of tumor suppressors such as p53 and BRCA2. The inhibition of Plk1 by small molecules or siRNA has been shown to interfere with several stages of mitosis. Therefore, inhibition of Plk1 offers an opportunity to treat cancer with a targeted anti-mitotic approach that will inhibit several important regulatory events in tumor cells.
Cyclacel Pharmaceuticals has employed high throughput screening, in silico screening and de novo ligand design approaches to discover multiple Plk1 inhibitor series. Our lead series includes potent and highly selective Plk1 inhibitors with broad anti-proliferative activity across a range of tumor cell lines. Use of intracellular biomarkers during lead optimization has ensured on-target activity. Compounds in the series are highly active in xenograft models of human cancers when dosed orally.
Non-oncology Programs
Our expertise in cell cycle biology has potential applications in a number of diseases outside of cancer. We have developed compound series with potential for use in several other diseases, including kidney disease, Type 2 diabetes and HIV/AIDS.
Inflammatory Kidney Disease and CDK inhibitors
As in cancer, certain kidney diseases are characterized by abnormal cell proliferation and dysregulation of the cell cycle. Glomerulonephritis is a major cause of kidney failure or End-Stage Renal Disease (ESRD), the treatment of which requires dialysis or kidney transplantation. Approximately $17 billion is spent annually to treat ESRD in the USA alone, one of few medical conditions to have received dedicated funding by act of Congress. Glomerulonephritis is often associated with other conditions which lead to kidney injury, such as viral infection, Systemic Lupus Erythematosus and exposure to toxic substances. In multiple preclinical studies, using seliciclib and second generation CDK inhibitors such as CYC065, Cyclacel Pharmaceuticals has demonstrated that the pharmacological inhibition of certain CDKs blocks or slows the progression of chronic and acute forms of glomerulonephritis.
GSK-3 Inhibitors in Type 2 Diabetes
Cyclacel Pharmaceuticals has developed lead compounds that inhibit the Glycogen Synthase Kinase-3, a target that plays an important role in controlling the body's glucose levels. Research indicates that GSK-3 is inhibited in healthy patients as part of the signaling pathway triggered by insulin when it binds to its receptor, but in patients with adult onset or Type 2 Diabetes, GSK-3 is not inhibited because the insulin receptor is not operating properly. In contrast with other GSK-3 inhibitors, our compounds do not induce the accumulation of beta-catenin, a protein associated with tumor growth.
HIV Cell Cycle Inhibitors
Cyclacel Pharmaceuticals has designed a number of compounds that inhibit cellular replication of the HIV/AIDS virus by blocking the replication of HIV/AIDS infected cells. Research suggests that our compounds act by inhibition of CDKs required for viral replication, providing a distinct approach to viral treatment because the compounds act on the host target as opposed to a viral target. This program builds on a body of literature that suggests that CDK inhibitors have been effective in a number of HIV/AIDS models in preclinical studies.
