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The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for
Bryce A Harrison1, James E Dowling1, Matthew G Bursavich1
1Chemistry, Morphic Therapeutic, Waltham, Massachusetts 02451, United States.
Journal of Medicinal Chemistry
|October 24, 2024
Summary
Researchers identified MORF-627, a selective inhibitor of integrin αvβ6, showing promise for fibrotic diseases like idiopathic pulmonary fibrosis. Despite good oral pharmacokinetics, toxicity halted its development, but it remains a valuable research tool.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Discovery
Background:
- Integrin αvβ6 is a key target for treating fibrotic diseases, including idiopathic pulmonary fibrosis.
- Stabilizing the bent-closed conformation of integrins is a strategy for developing potent inhibitors.
Purpose of the Study:
- To identify and optimize selective inhibitors of integrin αvβ6.
- To develop a potential therapeutic agent for fibrotic conditions.
Main Methods:
- Screening of a small compound library targeting integrin αvβ6.
- Structure-based drug design utilizing crystal structures.
- Free energy perturbation (FEP+) calculations for potency and selectivity enhancement.
- Pharmacokinetic (PK) parameter optimization.
Main Results:
- Hit compounds binding the bent-closed conformation of αvβ6 were identified.
- Development candidate MORF-627, a selective αvβ6 inhibitor with good oral PK, was discovered.
- MORF-627 demonstrated toxicity in a non-human primate safety study, preventing further clinical development.
Conclusions:
- MORF-627 is a potent and selective inhibitor of integrin αvβ6, useful for biological studies.
- Targeting integrin αvβ6 remains a promising strategy for fibrotic disease treatment.
- Further research is needed to overcome toxicity issues for therapeutic development.
