Integrins in Human Disease
The heterodimeric integrins family of receptors modulate cellular shape and cell adhesion to the extracellular matrix in response to extrinsic and intrinsic cues.
Integrin signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.
The integrin receptor exclusively can signal a cell bi-directionally, both “inside-out” and “outside-in.” Thus, they mediate cell migration by transmitting forces from the extracellular matrix to the cytoskeleton and regulate cytoskeletal organization to achieve shape changes needed during cell migration.
Integrins are expressed on the surface of most of human cells. Their pathology contributes to a diverse set of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration and various autoimmune and chronic inflammation diseases.
The role of integrins as drug targets has long been recognized and five injectable integrin inhibitors have been approved by the Food and Drug Administration for the treatment of inflammatory bowel disease (Entyvio®, Tysabri®), multiple sclerosis (Tysabri®), psoriasis (Raptiva®) and acute coronary syndrome (Reopro®, Aggrastat®, Integrilin®).
However, there has been a notable absence of therapeutic success with orally bioavailable integrin inhibitors that either didn’t improve or exacerbate patient outcomes.
Scientific findings in the Springer lab have shed light on the features of the productive small-molecule integrin inhibitor, enabling for the first time true small molecule antagonists dubbed super-antagonists.
We have identified at least 16 integrin targets of pharmacological relevance in inflammation, fibrosis, oncology and vascular disease.