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Site-Directed Immobilization of Bone Morphogenetic Protein 2 to Solid Surfaces by Click Chemistry
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Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.

Lara S Kallander1, David Washburn1, Mark A Hilfiker1

  • 1Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, and Platform Technology and Sciences, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, United States.

ACS Medicinal Chemistry Letters
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PubMed
Summary
This summary is machine-generated.

Bone Morphogenetic Protein 1 (BMP1) inhibition offers a novel fibrosis treatment. Researchers developed selective BMP1 inhibitors, optimizing for subcutaneous delivery to manage drug interaction risks.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Bone Morphogenetic Protein 1 (BMP1) is a zinc metalloprotease essential for collagen formation.
  • BMP1 activity is implicated in fibrotic diseases.
  • Targeting BMP1 presents a therapeutic strategy for fibrosis.

Purpose of the Study:

  • To discover and develop novel small molecule inhibitors of BMP1.
  • To explore structure-activity relationships for BMP1 inhibitors.
  • To identify a tool compound for in vivo studies and assess drug-drug interaction risks.

Main Methods:

  • Discovery of a novel class of reverse hydroxamate BMP1 inhibitors.
  • Cocrystallization of inhibitors with BMP1 to determine binding modes.
  • Structure-guided optimization of lead compounds.
  • In vitro and in vivo evaluation of tool compounds for efficacy and selectivity.
  • Assessment of cytochrome P450 inhibition for drug-drug interaction potential.

Main Results:

  • A unique binding mode was identified, targeting the nonprime side of the BMP1 active site.
  • Structure-guided modifications yielded potent and selective BMP1 inhibitors.
  • An orally bioavailable tool compound was identified with selectivity over other metalloproteases.
  • Irreversible inhibition of cytochrome P450 3A4 was observed for this chemical class.
  • Optimization led to a compound suitable for subcutaneous administration to mitigate drug-drug interactions.

Conclusions:

  • Novel reverse hydroxamate inhibitors of BMP1 were successfully developed.
  • The unique binding mode allows for metalloprotease selectivity.
  • A tool compound was generated for in vivo research.
  • Subcutaneous delivery is recommended for this class of inhibitors to manage drug-drug interaction risks associated with CYP450 inhibition.