Bryce A. Harrison, James E. Dowling, Matthew G. Bursavich, Dawn M. Troast, Katherine M. Chong, Kristopher N. Hahn, Cheng Zhong, Kristen M. Mulvihill, Hanh Nguyen, Meghan F. Monroy, Qi Qiao, Brian Sosa, Siavash Mostafavi, Inese Smukste, Dooyoung Lee, Laura Cappellucci, Elizabeth H. Konopka, Patrycja Nowakowski, Lukasz Stawski, Mayra Senices, Minh Hai Nguyen, Parmita S. Kapoor, Lia Luus, Andrew Sullivan, Andrea Bortolato, Mats Svensson, Eugene R. Hickey, Kyle D. Konze, Tyler Day, Byungchan Kim, Ana Negri, Aleksey I. Gerasyuto, Terence I. Moy, Min Lu, Adrian S. Ray, Liangsu Wang, Dan Cui, Fu-Yang Lin, Blaise Lippa, Bruce N. Rogers
{"title":"发现治疗纤维化的高选择性构象型齐聚物整合素 αvβ6 抑制剂 MORF-627","authors":"Bryce A. Harrison, James E. Dowling, Matthew G. Bursavich, Dawn M. Troast, Katherine M. Chong, Kristopher N. Hahn, Cheng Zhong, Kristen M. Mulvihill, Hanh Nguyen, Meghan F. Monroy, Qi Qiao, Brian Sosa, Siavash Mostafavi, Inese Smukste, Dooyoung Lee, Laura Cappellucci, Elizabeth H. Konopka, Patrycja Nowakowski, Lukasz Stawski, Mayra Senices, Minh Hai Nguyen, Parmita S. Kapoor, Lia Luus, Andrew Sullivan, Andrea Bortolato, Mats Svensson, Eugene R. Hickey, Kyle D. Konze, Tyler Day, Byungchan Kim, Ana Negri, Aleksey I. Gerasyuto, Terence I. Moy, Min Lu, Adrian S. Ray, Liangsu Wang, Dan Cui, Fu-Yang Lin, Blaise Lippa, Bruce N. Rogers","doi":"10.1021/acs.jmedchem.4c01851","DOIUrl":null,"url":null,"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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"60 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis\",\"authors\":\"Bryce A. Harrison, James E. Dowling, Matthew G. Bursavich, Dawn M. Troast, Katherine M. Chong, Kristopher N. Hahn, Cheng Zhong, Kristen M. Mulvihill, Hanh Nguyen, Meghan F. Monroy, Qi Qiao, Brian Sosa, Siavash Mostafavi, Inese Smukste, Dooyoung Lee, Laura Cappellucci, Elizabeth H. Konopka, Patrycja Nowakowski, Lukasz Stawski, Mayra Senices, Minh Hai Nguyen, Parmita S. Kapoor, Lia Luus, Andrew Sullivan, Andrea Bortolato, Mats Svensson, Eugene R. Hickey, Kyle D. Konze, Tyler Day, Byungchan Kim, Ana Negri, Aleksey I. Gerasyuto, Terence I. Moy, Min Lu, Adrian S. Ray, Liangsu Wang, Dan Cui, Fu-Yang Lin, Blaise Lippa, Bruce N. Rogers\",\"doi\":\"10.1021/acs.jmedchem.4c01851\",\"DOIUrl\":null,\"url\":null,\"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. 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The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.