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Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)
Yun Ding1, Heather O'Keefe1, Jennifer L DeLorey2
1Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
ACS Medicinal Chemistry Letters
|August 20, 2015
Summary
Researchers discovered new osteoarthritis drugs targeting ADAMTS-4 using DNA-encoded Library Technology. Potent and selective inhibitors were identified, offering a novel therapeutic approach without zinc-binding activity.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Drug Discovery
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown.
- Aggrecan degradation, mediated by enzymes like ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), is a key pathological process in OA.
- ADAMTS-4 has emerged as a significant therapeutic target for OA treatment.
Purpose of the Study:
- To identify novel inhibitors of ADAMTS-4 using DNA-encoded Library Technology (ELT).
- To explore structure-activity relationships (SAR) for optimizing inhibitor potency and selectivity.
- To develop potential therapeutic agents for osteoarthritis.
Main Methods:
- Affinity selection was employed using a DNA-encoded triazine library against ADAMTS-4.
- Structure-activity relationship studies were conducted based on the selection data.
- Inhibitor potency (IC50) and selectivity were evaluated against related proteases.
Main Results:
- Novel ADAMTS-4 inhibitors were successfully identified through ELT.
- Structure-activity relationship studies led to potent and highly selective compounds.
- One exemplary inhibitor demonstrated an IC50 of 10 nM against ADAMTS-4 with over 1000-fold selectivity against ADAMTS-5, MMP-13, TACE, and ADAMTS-13.
- The identified inhibitors lack obvious zinc-ligand functionalities.
Conclusions:
- DNA-encoded Library Technology is effective for identifying novel ADAMTS-4 inhibitors.
- Potent and selective inhibitors targeting ADAMTS-4 were discovered, representing a promising therapeutic strategy for osteoarthritis.
- The novel inhibitors' lack of zinc-binding functionality may offer advantages in terms of safety and mechanism of action.
