AI Article Synopsis
- - Receptor tyrosine kinases (RTKs) are important targets for developing new cancer drugs, but most existing inhibitors work by blocking the main binding sites for ligands and substrates.
- - The chemical SSR128129E (SSR) is a new type of RTK inhibitor that binds to a different site on the fibroblast growth factor receptor (FGFR), allowing it to inhibit signaling without interfering with the binding of its normal ligands.
- - SSR shows potential for treating hard-to-target tumors and arthritis, demonstrating that orally-taken, allosteric RTK modulators could lead to better cancer treatment options.
Article Abstract
Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.
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| http://dx.doi.org/10.1016/j.ccr.2013.02.019 | DOI Listing |
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