PHILADELPHIA (June 26, 2023) — Integrins are a type of protein found on the surface of all cells that helps them communicate with and attach to nearby cells. Under normal circumstances, they play a key role in cell growth and other cellular functions that are beneficial, including cell migration, blood clotting, and immune responses.
But in other cases, they can assist in the growth and spread of cancer, so there has been intense research efforts over the past few years to develop drugs that target integrins. Researchers from Fox Chase Cancer Center published a paper today that contributes to this important field of research.
“This study offers new insights into the possible development of intracellular integrin inhibitors for diseases caused by faulty integrin signaling, including cancer, cardiovascular disease, and many auto-immune disorders,” said Jinhua Wu, PhD, an associate professor in the Cancer Signaling and Microenvironment research program at Fox Chase.
The study, “Inhibition of Talin-Induced Integrin Activation by a Double-Hit Stapled Peptide,” was published today in Structure.
Integrin research is considered so important and promising that last year a team of scientists received the prestigious Lasker Basic Medical Research Award for their discovery and characterization of the proteins. There have been several anti-integrin drugs approved and marketed, but they often cause severe adverse effects, underscoring the need for new drugs that can affect integrin function with minimal side effects.
Tong Gao, PhD, a postdoctoral associate in Wu’s lab who was the main contributor and first author on the study, said it focused on an innovative integrin inhibitor design that targets the interaction between integrin and talin, an adaptor protein that triggers integrin activation. This activation occurs through an inside-out signaling pathway that can be driven by RAP1-interacting adaptor molecule (RIAM) through its interaction with talin at two sites.
“A helical talin-binding segment (TBS) in RIAM interacts with both sites in talin, leading to integrin activation. The bi-specificity inspires a ‘double-hit’ strategy for inhibiting talin-induced integrin activation,” the authors wrote. The new inhibitor, which has been dubbed S-TBS, is also the first talin peptidomimetic inhibitor designed based on experimental structures, Wu said.
“We anticipate,” the authors wrote, “that this approach of inhibitor design by targeting multiple events in a pathway will not only lead to the discovery of novel anti-integrin drugs” but also help identify new intracellular targets and facilitate the development of related peptidomimetic inhibitors to improve outcomes for patients.