Uses Piperlongumine as an E3 Ligase Ligand to Facilitate the Degradation of Cancer-Associated Proteins of Interest
This naturally occurring compound with anti-cancer properties has the potential to revolutionize cancer treatment by providing tailored therapies with reduced side effects. Cancer remains a significant health issue in the United States, with considerable unmet medical needs. Available cancer treatments such as chemotherapy and radiation therapy are limited by factors including toxicity and drug resistance. Hence, it is necessary to develop more accurate and effective cancer treatments that produce fewer side effects. An emerging form of cancer therapy involves using proteolysis-targeting chimeras (PROTACs). PROTACs are bifunctional molecules consisting of two covalently linked components – a ligand that targets a protein of interest and a ligand that recruits an E3 ligase, which facilitates the degradation of the target protein. By hijacking the natural cellular protein degradation process, PROTACs can eliminate undesirable cancer-associated proteins, such as kinases, with greater precision than traditional therapies. The use of PROTACs is limited by the absence of diverse ligands for E3 ligases, an essential component of PROTACs.
Researchers at the University of Florida have identified Piperlongumine, a naturally occurring compound with anti-cancer properties, as a possible ligand for E3 ligases. PROTACs have been synthesized by conjugating Piperlongumine to a CDK9 inhibitor (SNS-032) currently used as a cancer therapeutic. A lead conjugate, 955, has been discovered to potently degrade CDK9 and CDK10 in a ubiquitin-proteasome dependent manner. This advancement in PROTAC technology has the potential to revolutionize cancer treatment by addressing the scarcity of ligands for E3 ligases, leading to tailored cancer therapies with reduced side effects.
Application
Biological conjugate of E3 ligase ligand and CDK9 inhibitor that targets and degrades cancer-associated proteins of interest
Advantages
- Piperlongumine binds to multiple E3 ligases, allowing the design of PROTACS that target a wider range of proteins
- Piperlongumine is a natural occurring compound, reducing the likelihood of PROTAC adverse effects on normal human cells
- Piperlongumine-based PROTAC (conjugate 955) exhibits increased degradation of CDK9 and CDK10 in MOLT4 cells, enabling selective inhibition of key proteins involved in cancer progression
Technology
PROTACs, an emerging form of cancer therapy, hijack the cellular ubiquitin-proteasome system (UPS) and degrade cancer-related proteins of interest. They are bifunctional molecules consisting of two pharmacophores. The first pharmacophore is a ligand that targets a cancer-associated protein of interest, while the second pharmacophore recruits an E3 ligase that facilitates the polyubiquitination and subsequent proteasome degradation of the target protein. Piperlongumine, a naturally occurring compound with anti-cancer and anti-aging properties, has been discovered to serve as the second pharmacophore due to its binding ability to bind several E3 ligases. CDK9 inhibitors such as SNS-032 are used as cancer therapeutics and can serve as the second pharmacophore in a PROTAC. UF researchers covalently conjugated Piperlongumine to SNS-032 and identified the most potent conformation, PROTAC conjugate 955. Conjugate 955 is a potent anticancer therapeutic as it recruits Kelch-like ECH-associated protein 1 (KEAP1) E3 ligase which mediates the proteasomal degradation of CDK9 and CDK10. These results show that Piperlongumine is a distinct E3 ligase ligand that can be used to synthesize effective anticancer PROTACs.
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