CYC065: Targeting Multiple Myeloma with a New Generation CDK Inhibitor in Preclinical Trials

The research focuses on the development of new treatments for multiple myeloma (MM), a type of blood cancer that is currently considered incurable. The study centers on cyclin-dependent kinases (CDKs), enzymes that play a key role in cell cycle regulation and are overexpressed in MM. CDKs are being targeted with CDK inhibitors, which have shown potential in treating cancer.

CYC065, a potent CDK inhibitor and an advanced version of seliciclib, has been found to be particularly effective against CDKs 2, 5, and 9. These CDKs are crucial for cell cycle progression and RNA polymerase II regulation. The drug has demonstrated success in preclinical studies for breast cancer and leukemia and has now been evaluated in MM.

In vitro tests on seven MM cell lines revealed that CYC065 was cytotoxic to both chemotherapy-sensitive and -resistant cells, with an IC50 ranging from 0.06 to 2μM within 24 to 48 hours. The drug also hindered the cell proliferation stimulated by bone marrow stromal cells and certain cytokines. Apoptosis induction was confirmed in MM1.s cells starting at 9 hours with a concentration of 0.125μM, leading to 82% cell death after 48 hours. The cell cycle analysis showed an increase in the subG1 phase, indicating cell death, and western blot analysis confirmed the drug's apoptotic effect through the activation of caspases and PARP cleavage.

Additionally, CYC065 was tested on primary CD138+ cells from three patients with refractory MM, showing its effectiveness at the same concentration and time points. While toxicity evaluations in peripheral blood mononuclear cells (PBMCs) from healthy donors are ongoing, the results so far support the drug's potential in treating MM at low nanomolar concentrations.

The study also includes disclosures related to the affiliations and financial interests of the researchers involved, indicating potential conflicts of interest with pharmaceutical companies and research funding sources. Further studies are needed to understand the drug's mechanism of action and its potential for clinical application in MM treatment.