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

Autor:	Harrison BA; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Dowling JE; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Bursavich MG; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Troast DM; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Chong KM; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Hahn KN; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Zhong C; Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Mulvihill KM; CMC, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Nguyen H; CMC, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Monroy MF; Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Qiao Q; Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Sosa B; Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Mostafavi S; Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Smukste I; DMPK, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Lee D; DMPK, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Cappellucci L; Screening Biology, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Konopka EH; Screening Biology, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Nowakowski P; Screening Biology, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Stawski L; Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Senices M; Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Nguyen MH; Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Kapoor PS; Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Luus L; Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Sullivan A; Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Bortolato A; Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Svensson M; Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Hickey ER; Medicinal Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Konze KD; Medicinal Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Day T; Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Kim B; Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Negri A; Computational Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Gerasyuto AI; Medicinal Chemistry, Therapeutics Group, Schrödinger, New York, New York 10036, United States., Moy TI; Screening Biology, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Lu M; Fibrosis, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Ray AS; Biology and Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Wang L; Biology and Translational Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Cui D; DMPK, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Lin FY; Molecular and Cellular Sciences, Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Lippa B; Morphic Therapeutic, Waltham, Massachusetts 02451, United States., Rogers BN; Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Oct 24. Date of Electronic Publication: 2024 Oct 24.
DOI:	10.1021/acs.jmedchem.4c01851
Abstrakt:	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.
Databáze:	MEDLINE
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