9CZ7

Crystal structure of integrin avb6 headpiece in complex with compound 12

This is a non-PDB format compatible entry.

Summary for 9CZ7

• Entry DOI: 10.2210/pdb9cz7/pdb
• Related: 9CZA 9CZD 9CZF
• Descriptor: Integrin alpha-V heavy chain, MAGNESIUM ION, (2S)-phenyl{(3S)-3-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butoxy]pyrrolidin-1-yl}acetic acid, ... (14 entities in total)
• Functional Keywords: avb6 integrin, fibrosis, idiopathic pulmonary fibrosis, free energy perturbation, cell adhesion, cell adhesion-immune system complex, cell adhesion/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 171231.73

Authors

Monroy, M.F.,Qiao, Q.,Lin, F.Y. (deposition date: 2024-08-04, release date: 2024-11-13, Last modification date: 2024-11-27)

Primary citation

Harrison, B.A.,Dowling, J.E.,Bursavich, M.G.,Troast, D.M.,Chong, K.M.,Hahn, K.N.,Zhong, C.,Mulvihill, K.M.,Nguyen, H.,Monroy, M.F.,Qiao, Q.,Sosa, B.,Mostafavi, S.,Smukste, I.,Lee, D.,Cappellucci, L.,Konopka, E.H.,Nowakowski, P.,Stawski, L.,Senices, M.,Nguyen, M.H.,Kapoor, P.S.,Luus, L.,Sullivan, A.,Bortolato, A.,Svensson, M.,Hickey, E.R.,Konze, K.D.,Day, T.,Kim, B.,Negri, A.,Gerasyuto, A.I.,Moy, T.I.,Lu, M.,Ray, A.S.,Wang, L.,Cui, D.,Lin, F.Y.,Lippa, B.,Rogers, B.N.
The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin alpha v beta 6 Inhibitor for Fibrosis.
J.Med.Chem., 67:18656-18681, 2024

PubMed Abstract: Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

PubMed: 39446989
DOI: 10.1021/acs.jmedchem.4c01851

Experimental method

X-RAY DIFFRACTION (2.57 Å)