Research & Development
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.
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.
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.
Seliciclib in Rheumatoid Arthritis (an investigator sponsored trial)
Seliciclib is being evaluated in an investigator sponsored trial (IST) to treat rheumatoid arthritis (RA) in patients who do not respond adequately to existing treatments. Newcastle University,UK, together with their collaborators at the Universities of Birmingham, UK, and Glasgow, UK, believe that seliciclib may offer a novel therapeutic approach to the treatment of RA by targeting the quasi-malignant synovial fibroblasts, the key pathological cell type responsible for joint destruction. Conventional therapies for RA, called disease-modifying anti-rheumatic drugs (DMARDs), slow or halt the progress of the disease by dampening the immune system. In addition to its potential effects in reducing cytokine production, seliciclib is also expected to inhibit the aberrant proliferation and reduce the survival of synovial fibroblasts, as well as limiting the production of enzymes responsible for joint destruction. Seliciclib could therefore succeed in directly intervening in the pathological process, and provide significant improvement in the outcomes of patients with RA.
The trial is a multi-center, single arm, two-stage study across three clinical sites and is being led by Professor John Isaacs at Newcastle University. The study will recruit approximately forty patients with moderate to severe RA disease activity, and will be conducted in two parts. The primary objectives of the study are to establish the MTD, using a Bayesian Continuous Reassessment Method (Part 1; 4 weeks dosing) and to determine the response to treatment with seliciclib in combination with anti-TNF monotherapy (Part 2; 12 weeks). Secondary objectives include assessing the relationship between response, PK and PD markers in peripheral blood and synovium, and the impact of seliciclib on RA-associated autoantibodies. The study is supervised by an IDMC, the charter of which contains stopping rules for safety and recommendations for appropriate follow-up. The study is listed on international registries under ISRCTN: 36667085 and EUDRACT: 2014-001339-35.
Seliciclib in Cushing's Disease (an investigator sponsored trial)
Seliciclib is being evaluated in an investigator sponsored trial (IST) to treat Cushing's disease (Cd) Clinicians at Cedars Sinai Medical Center, Los Angeles, USA have demonstrated preclinical proof-of-concept that seliciclib is uniquely effective amongst CDK inhibitors in resolving the disease, with dual effects on pituitary growth and adrenocorticotropin (ACTH) production. Cd is an endocrine disorder caused by ACTH-producing pituitary tumours, often leading to obesity, diabetes, hypertension, osteoporosis and increased mortality rate if inadequately controlled. Cell cycle dysregulation is a common feature of pituitary tumours, including upregulation of cyclin E, specifically seen in tumours of the corticotroph lineage, such as in Cd.
The trial is a Phase II proof-of-concept, open-label, single arm study to assess the safety and efficacy of seliciclib in Cd. Sixteen patients with de novo, persistent or recurrent Cd will receive seliciclib for 4 weeks prior to standard-of-care treatment. The primary objective is to establish the efficacy of seliciclib on normalizing urinary free cortisol levels in patients with Cd.