Fadraciclib is an investigational drug for various cancers. It belongs to a class of medications known as cyclin-dependent kinase (CDK) inhibitors. These inhibitors work by interfering with the activity of specific enzymes that regulate cell growth and division. Fadraciclib is being developed by Cyclacel Pharmaceuticals, Inc., and represents an advancement over previous CDK inhibitors.
How Fadraciclib Works
Fadraciclib targets and inhibits Cyclin-Dependent Kinase 9 (CDK9), along with CDK2. CDK9 is an enzyme that regulates gene transcription, the process of copying genetic information from DNA into RNA. Specifically, CDK9 helps control RNA Polymerase II (RNAPII) by adding phosphate groups to it, phosphorylation. This phosphorylation is necessary for RNAPII to produce messenger RNA (mRNA), which directs protein creation essential for cell growth and survival.
When fadraciclib inhibits CDK9, it prevents RNAPII from being properly phosphorylated. This disruption stops the production of new mRNA, blocking the synthesis of proteins cancer cells need to grow and survive. A primary protein affected is Myeloid Cell Leukemia 1 (MCL1), a pro-survival protein often overexpressed by cancer cells to avoid programmed cell death. Since MCL1 protein is rapidly turned over, CDK9 inhibition quickly decreases MCL1 levels, triggering cancer cell self-destruction through apoptosis. Fadraciclib also inhibits CDK2, which is involved in cell cycle progression and can contribute to MCL1 stabilization, further enhancing its ability to induce apoptosis in sensitive cancer cells.
Cancers Targeted by Fadraciclib
Fadraciclib is being investigated for a range of cancers, including solid tumors and blood cancers. For solid tumors, it is being explored against types such as breast cancer, ovarian cancer, pancreatic cancer, lung cancer, and colorectal cancer. Triple-negative breast cancer (TNBC), an aggressive form of breast cancer, is of interest due to its elevated CDK2/cyclin E activity, amplified MCL1, and high MYC oncogene levels, all influenced by fadraciclib.
For blood cancers (hematological malignancies), fadraciclib is studied in conditions like acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and myelodysplastic syndrome (MDS). High MCL1 levels are often observed in these leukemias and are associated with poor patient outcomes. Early research suggests fadraciclib may be effective in leukemia cell models with specific genetic markers, such as mixed lineage leukemia (MLL) gene status and BCL2 family protein levels. Its ability to deplete MCL1 makes it a promising candidate, especially when combined with other agents targeting different pro-survival pathways, like BCL2 inhibitors.
Current Research and Development
Fadraciclib is currently undergoing clinical development, involving studies in human volunteers to assess safety and effectiveness. Studies are divided into phases. Phase 1 trials focus on determining a safe dosage and identifying side effects. Phase 2 trials evaluate effectiveness in specific conditions and continue to monitor safety.
It is being evaluated in multiple Phase 1/2 clinical trials, including one (NCT04983810) investigating oral fadraciclib in advanced solid tumors and lymphomas. Other trials (NCT03739554, NCT04017546) explore fadraciclib in hematological malignancies like relapsed or refractory CLL, AML, or MDS. Some studies also evaluate fadraciclib in combination with approved therapies, such as the BCL2 inhibitor venetoclax, especially in leukemia patients. Initial results from the Phase 2 proof-of-concept study are expected by the end of 2024. As an investigational drug, its future progression depends on these and further clinical trial outcomes, which will determine its potential for regulatory approval and broader use.