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Protein kinases, enzymes that catalyze reversible phosphorylation, are important players in cell signaling and are often dysregulated in cancer. For this reason, kinase inhibitors are popular cancer drugs that work by locking kinases in their active or inactive form, depending on function.

Kinase inhibitors that act on the active conformation, also known as adenosine triphosphate, or ATP,–competitive inhibitors, occupy the ATP binding pocket of the kinase domain, where the catalytic reaction takes place, and lock kinases in an active form. Because kinase domains across various proteins are well conserved, scientists can relatively easily develop ATP–competitive inhibitors that bind a variety of kinase targets.

 

However, these inhibitors can be less effective than their counterparts that bind to other parts of the kinase and lock them in the inactive conformation. Binding to the ATP pocket only inhibits their enzymatic activity, but not their other functions like scaffolding, which may promote tumorigenesis. 

In a recent published in the Journal of Biological Chemistry, an international group of scientists reported a new kinase inhibitor, NXP900, that targets the inactive form of , or SFKs. The team showed that head and neck as well as esophageal squamous cell carcinomas are highly sensitive to NXP900 treatment both in cell culture and animals. The drug is currently in clinical trials.  

“It was surprising to me how responsive a lot of these cell lines were to NXP900,” , senior investigator at the National Institutes of Health’s National Cancer Institute and the study’s corresponding author, said.

Brognard said his group became interested in head and neck as well as esophageal squamous cell carcinomas because these cancers have a shared genetic component: sequence amplification of an SFK called Yes. Existing SFK Src kinase inhibitors like are ineffective and approved immunotherapies like have very low success rates in these types of cancer. So, patients are stuck with radiotherapy or chemotherapy, which can produce many unpleasant side effects.

Patients with these conditions are desperate for effective treatments, he said.

“One of the biggest discoveries of this paper was how we identified a patient cohort that could really benefit from NXP900,” Brognard said.

, a postdoctoral fellow at NCI and lead author of the paper, and Brognard said that NXP900 targets multiple members of the SFK, including Yes, Src and Lck. According to Brognard, this approach, commonly referred to as “polypharmacology,” goes a step further beyond simple kinase inhibitors.  

Kinases that are closely related can compensate for each other and drive drug resistance, Brognard said. For example, if we target Yes alone, we will likely observe resistance arising through compensation by other SFKs like Src or Lck, he said.

“Resistance will probably eventually still occur,” said Brognard. “But we can postpone it by targeting multiple cancer drivers simultaneously.”

Dash said that future research will home in on the molecular mechanisms of NXP900.

“We saw that some of the squamous cell carcinoma lines that we tested were sensitive to NXP900 while others were resistant,” she said. “We want to know why.”