Alpha 4 beta 7 (α4ß7) is a powerful signaling molecule embedded in the cell membranes of immune cells and is an established target for inflammatory bowel disease. Vedolizumab, which is approved for the treatment of ulcerative colitis and Crohn’s disease, is an anti-α4ß7 monoclonal antibody that is given to patients through intravenous infusion. We believe that there is an unmet need for convenient oral therapies for these indications due to their chronic nature.
The dimeric nature of integrins (which consist of one alpha protein subunit and one beta protein subunit), as well as the existence of chemical starting points, enabled us to apply DELSCAPE to identify potent and highly selective small molecule inhibitors of α4ß7. We believe that the high selectivity for α4ß7 over α4ß1 is a key feature of ENTYVIO and will be critical for the development of a small molecule oral therapeutic. Our lead compounds demonstrate over 1,000-fold selectivity for α4ß7 over α4ß1 and our program is in the lead optimization stage.
We are also pursuing antagonists of the alpha V (αV) family of integrins with the intent of developing therapeutic candidates for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases. Increased expression of the integrins alpha V beta 1 (αVß1) and alpha V beta 6 (αVß6) has been observed in patients with IPF and it has been demonstrated that increased levels of αVß1 and αVß6 drive increased activation of TGF-ß, a potent pro-fibrotic mediator. Preclinical data indicates that inhibitors of αVß1 and αVß6 have potential as therapeutics for the treatment of IPF and other fibrotic diseases by reducing TGF-ß activation.
DELSCAPE enabled us to identify potentially potent inhibitors of αVß1 and αVß6 with a variety of selectivity profiles ranging from αVß1-selective, to dual-selective, to αVß6-selective. In the case of αV integrins, the optimal selectivity profile between αVß1 andαVß6 has not been established in the clinic. We are therefore advancing multiple leads with different selectivity profiles. Our αVß1/αVß6 program is in the lead optimization stage.