Synthesis and Biological Evaluation of Cyclobutane-Based β3 Integrin Antagonists: A Novel Approach to Targeting Integrins for Cancer Therapy

SIMPLE SUMMARY: The integrin family of cell surface proteins plays an important role in the development and spread of cancers. Therefore, drugs which inhibit integrins should make effective cancer treatments. Most potential drugs developed so far target a single integrin and have not proved effective at treating cancer in human studies. Our research aims to develop more effective drugs by targeting two related integrins. This paper describes how these potential drug molecules are made, allowing chemists to make better compounds in the future, and describes the anti-integrin effects of the new compounds. Together this information will lead to the future design and development of better anticancer drugs. ABSTRACT: The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the β3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvβ3 and αIIbβ3 are important anticancer targets, most integrin antagonists developed to target the β3 integrins are highly selective for αvβ3 or αIIbβ3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic β3 integrin antagonist. These new antagonists combine a high activity against αvβ3 with a moderate affinity for αIIbβ3, providing the first evidence for a new approach to integrin targeting in cancer.