Sandbox reserved CDK2 Oxindole Inhibitor

• Many patients are placed on chemotherapy for the treatment of cancer. One of the concerns with these patients is the chemotherapy-induced alopecia (CIA). Alopecia, or hair loss, is an esthetic concern to patients and can be emotionally devastating. Researchers have been investigating ways in which to inhibit alopecia. A possible way is through the inhibition of CDK2.
• Chemotherapy agents that cause CIA attack rapidly dividing cells. The cells that are responsible for growing hair are considered to be “rapidly dividing,” thus are very sensitive to these chemotherapy agents.
• CDK2 is a positive regulator of the eukaryotic cell cycle progression and is a catalytic unit that helps the cell progress from the G1 phase to the S phase. CDK2 is thought to be a requirement in many cells for cell proliferation. This makes it an excellent protein to target to prevent CIA.
• The representation displayed is that of cyclin-dependent kinase 2 (CDK2) interacting with an oxindole inhibitor. The ligand pictured is the , 4-(5-bromo-2-oxo-2h-indol-3-ylazo)- benzenesulfonamide. is part of the Ser/Thr protein kinases. CDK2 is a positive regulator of the eukaryotic cell cycle progression and is a catalytic unit that helps the cell progress from the G1 phase to the S phase. ^[1]
• In the study “The Structure of Cyclin-Dependent Kinase 2 (CDK2) in Complex with an Oxindole Inhibitor,” researchers studied whether using a topical oxindole inhibitor would reduce the chemotherapy-induced alopecia (CIA). Alopecia is characterized by hair loss. By inhibiting the CDK2, the cell cycle is slowed and the sensitivity to the epithelium from many cell cycle-active antitumor agents is reduced. Thus, a reduction in hair loss can be possible. ^[2]
• The CDK2 is composed of a total of . The oxindole inhibitor interacts with CDK2 through a small located at the competiting with .
• The oxindole inhbitor is able to interact with CDK2's active site through four important sets of , thus slowing the cell cycle. The interactions include in a Pi-Pi, Pi-cation interaction, an interaction with in a hydrophobic interaction, and there are two sets of important hydrogen bonds: and . These interactions help the oxindole inhibitor bind to CDK2 and help it compete with adenosine triphosphate (ATP).
• CCL64 cells were plated and Taxol, Etoposide, Cisplatin, 5FU, or Doxorubicin was added. Some of the cells were also treated with the oxindole inhibitor. All of the cells were then fixed and stained and the optical density was used to determine the number of stained cells and compared to one another. The results showed that all of the cells were able to resist the toxic effect of the chemotherapy agent; Etoposide to a lesser extent.

References

1. ↑ [1]
2. ↑ Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe Jr RT, Griffin RJ, Harris PA, Hassell AM, Holmes WD, Hunter RN, Knick VB, Lackey K, Lovejoy B, Luzzio MJ, Murray D, Parker P, Rocque WJ, Shewchuk L, Veal JM, Walker DH, Kuyper LF. Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science. 2001 Jan 5;291(5501):134-7. PMID:11141566 doi:10.1126/science.291.5501.134