Integrins are cell adhesion molecules that play an important role in cancer cell migration and survival. These molecules are also valid therapeutic targets for many types of cancer. In a new , Versiti Blood Research Institute (VBRI) scientists developed a novel design for integrin inhibitors that have improved safety and efficacy for treating integrin-related diseases, such as cancer, autoimmune disease, and thrombosis.
“We discovered the non-activating feature of integrin inhibitors can be controlled by one unique atom in the compounds, which helps hold a critical water molecule to maintain the resting state of integrin,” said VBRI Senior Investigator Jieqing Zhu, PhD.
These results provide a general chemical principle for the design of integrin inhibitors that lack integrin-activating activity. According to Dr. Zhu, the drug design strategy can be applied to the whole integrin family and may revive the efforts of drug development aiming to target integrins in cancers.
An aspirational goal in the integrin field has been to create small-molecule integrin inhibitors that do not induce an activating conformational change. Scientists have taken this concept a step further by discovering that some compounds can suppress integrin opening by shifting the conformational ensemble toward the low-affinity closed states — a feature that may offer additional clinical benefit.
Small molecule integrin inhibitors have been under development for several decades with only a few successes. Many drug candidates, although showing high potency in the inhibition of integrin function in vitro, failed in clinical trials. Dr. Zhu explained that one of the potential reasons for the failure of these compounds is they induce basal level activation of their integrin targets, which may be toxic, especially when used chronically.
The research team noted that some integrin inhibitors, though not intentionally designed, fail to induce basal level integrin activation. By continuing to do high-resolution structural studies, they hope to discover the chemical basis that renders the non-activating feature of these integrin inhibitors.
“Due to the critical functions of integrin in the progress of many diseases, the development of integrin inhibitors has been a longstanding effort. We expect our discovery will help drug companies and academic researchers further their integrin inhibition studies and aid the development of new targeted therapies for cancer patients,” said Dr. Zhu.
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