2. Academic Validation
  3. The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis

The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis

  • J Med Chem. 2024 Nov 14;67(21):18656-18681. doi: 10.1021/acs.jmedchem.4c01851.
Bryce A Harrison 1,  James E Dowling 1,  Matthew G Bursavich 1,  Dawn M Troast 1,  Katherine M Chong 1,  Kristopher N Hahn 1,  Cheng Zhong 1,  Kristen M Mulvihill 2,  Hanh Nguyen 2,  Meghan F Monroy 3,  Qi Qiao 3,  Brian Sosa 3,  Siavash Mostafavi 3,  Inese Smukste 4,  Dooyoung Lee 4,  Laura Cappellucci 5,  Elizabeth H Konopka 5,  Patrycja Nowakowski 5,  Lukasz Stawski 6,  Mayra Senices 6,  Minh Hai Nguyen 6,  Parmita S Kapoor 6,  Lia Luus 7,  Andrew Sullivan 7,  Andrea Bortolato 8,  Mats Svensson 8,  Eugene R Hickey 9,  Kyle D Konze 9,  Tyler Day 8,  Byungchan Kim 8,  Ana Negri 8,  Aleksey I Gerasyuto 9,  Terence I Moy 5,  Min Lu 6,  Adrian S Ray 10,  Liangsu Wang 10,  Dan Cui 4,  Fu-Yang Lin 3,  Blaise Lippa 11,  Bruce N Rogers 11
Affiliations

Affiliations

  • 1 Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 2 CMC, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 3 Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 4 DMPK, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 5 Screening Biology, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 6 Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 7 Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 8 Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States.
  • 9 Medicinal Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States.
  • 10 Biology and Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
  • 11 Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
PMID: 39446989 DOI: 10.1021/acs.jmedchem.4c01851
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.

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