Targeting Cancer Cells by Focusing on Protein-Protein Interaction

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Scientists at the University of California, Riverside (UCR), say they have developed a new approach to targeting cancer cells that circumvents a challenge faced by currently available cancer drugs.

A cancer target is often a rogue protein that signals cancer cells to proliferate uncontrollably and invade organs. Modern cancer drugs have emerged that work by striking a tight bond between the drug and the amino acid cysteine, which reacts with specific organic functional groups to form a strong molecular bond.

Only a few new cancer drugs that target cysteine have been recently approved by the FDA, note the researchers who point out that a key challenge is that cysteine is rarely found within binding sites of cancer targets, limiting the application of this approach to only a few drug targets.

The UCR team has explored the development of drugs that target other potentially reactive amino acids, such as lysine, tyrosine, or histidine, which occur more often within the binding site of the target. The researchers also addressed another challenge: The target they used for proof of concept was a protein-protein interaction (PPI) target. PPIs represent a large class of possible therapeutic targets for which designing effective drugs is particularly difficult. This is because PPIs lack a well-defined and deep-binding pocket onto which drugs can be designed to bind tightly.

“To date, there is only one drug approved by the FDA that was designed to antagonize—block—a PPI target,” said Maurizio Pellecchia, PhD, a professor of biomedical sciences in the School of Medicine, who led the research. “Only a few others have entered clinical trials. Our approach provides novel and effective avenues to derive potent and selective PPI antagonists by designing drugs that can react with lysine, tyrosine, or histidine residues that are ubiquitously present at binding interfaces of PPIs.”

Results of the study (“Covalent Inhibitors of Protein-Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues”) appear in the Journal of Medicinal Chemistry.

“We have recently reported on a series of Lys-covalent agents targeting the BIR3 domain of the X-linked Inhibitor of Apoptosis Protein (XIAP) using a benzamide-sulfonyl fluoride warhead. Using XIAP as a model system, we further investigated a variety of additional warheads that can be easily incorporated into binding peptides, and analyzed their ability to form covalent adducts with lysine and other amino acids, including tyrosine, histidine, serine, and threonine, using biochemical and biophysical assays. Moreover, we tested aqueous, plasma stability, cell permeability, and cellular efficacy of the most effective agents,” write the investigators.

These studies identified aryl-fluoro sulfates as likely the most suitable electrophiles to effectively form covalent adducts with Lys, Tyr, and His residues, given that these agents were cell permeable, and stable in aqueous buffer and in plasma. Our studies contain a number of general findings that open new possible avenues for the design of potent covalent PPIs antagonists.”

Pellecchia, who holds the Daniel Hays chair in cancer research at UCR, explained that academic researchers, the biotechnology industry, and pharmaceutical companies are heavily pursuing the design of covalent drugs that bind irreversibly with their targets. Those that target cancer cells most often target cysteine because it is more reactive than all other amino acids in a protein target. Oncology drugs such as Osimertinib, Ibrutinib, Neratinib, and Afatinib have all been approved in very recent years by the FDA, he said, and all target a cysteine that is present on the binding site of their respective targets.

“Our work widens the available target space beyond cysteine,” he added. “Such covalent agents could represent significant stepping stones in the development of novel drug candidates against PPIs, which represent an untapped large class of therapeutic targets not only in oncology, but also in other conditions including neurodegenerative and inflammatory diseases.”

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