Research & Development

Other Programs

Seliciclib (CYC202)

Seliciclib is Cyclacel's first generation novel, small molecule inhibitor of CDK2/CDK9. Seliciclib is orally available and inhibits enzymes such as, CDK2/E, CDK2/A and CDK7. All these kinases are central to the process of cell division and cell cycle control and play pivotal roles in cancer cell growth and DNA damage repair. Inhibition of CDKs 2 and 9 may also correct aberrant cell cycle control in certain non-malignant diseases of proliferation.

Seliciclib exerts an anti-proliferative effect via several key mechanisms:

  • Selective downregulation of proliferative and survival proteins and upregulation of p53, leading to growth arrest or apoptosis;
  • Decreasing phosphorylation of Rb and modulating E2F transcriptional activity leading to growth arrest or apoptosis;
  • Inhibiting HR and NHEJ DNA repair pathways, resulting in synergy with DNA damaging agents; and
  • In sequence with chemotherapy, overcoming cell cycle related drug resistance.

Our expertise in cell cycle biology has potential applications in several diseases outside of cancer. Use of seliciclib have been expanded to explore diseases related to inflammation such as rheumatoid arthritis, and endocrine dysfunction, for example cushings disease.

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.

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 tumors, often leading to obesity, diabetes, hypertension, osteoporosis, and increased mortality rate if inadequately controlled. Cell cycle dysregulation is a common feature of pituitary tumors, including upregulation of cyclin E, specifically seen in tumors of the corticotroph lineage, such as Cd.

The trial is a Phase 2 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. Cedars-Sinai Medical Center has launched a Phase 2 multicenter study of seliciclib for the treatment of Cushing disease. The study is funded by FDA through the Orphan Products Clinical Trials Grants Program.

Research & Development