# Design, synthesis and biological activity of glycoconjugated ADAMTS5 exosite inhibitors: applications in osteoarthritis and ovarian cancer models

## TL;DR

This paper describes the design and testing of a new ADAMTS5 inhibitor that shows promise for treating osteoarthritis and ovarian cancer.

## Contribution

A new non-toxic ADAMTS5 inhibitor derivative was developed and shown to effectively reduce cartilage degradation and cancer cell migration.

## Key findings

- Compound 2 was tolerated at high concentrations and inhibited aggrecan degradation in OA cartilage.
- Compound 2 reduced directional ovarian cancer cell migration and pseudopod elongation.
- In silico analysis explained the differing biological activities between compound 4b and its derivative 2.

## Abstract

Pharmacological inhibition of the extracellular zinc metalloprotease A Disintegrin-like And Metalloprotease domain with Thrombospondin type I motifs 5 (ADAMTS5) has been proposed as a treatment for osteoarthritis (OA), a degenerative disease characterized by cartilage loss. More recently, ADAMTS5 has been implicated in ovarian cancer (OC), due to its essential role in promoting cell migration and association with poor prognosis. ADAMTS5 major substrates are the proteoglycans aggrecan and versican, which support the structural integrity of the cartilage and the tumor microenvironment. We have recently described a non-chelating arylsulfonamide glycoconjugate, compound 4b, as a selective ADAMTS5 inhibitor, and shown its effectiveness in an OC 3D model. Here, we modified the structure of 4b to improve its biological activity. We showed that, while 4b induces cytotoxicity in several cell lines as well as in porcine and human cartilage explants, its derivative 2 was tolerated at high micromolar concentrations and effective in inhibiting aggrecan degradation in human ex vivo OA explants and reducing directional OC cell migration and pseudopod elongation. In silico analyses provided a rationale behind the different biological activities of the two compounds. These findings highlight the potential of non-chelating glycoconjugated arylsulfonamides to treat pathologies characterized by excessive ADAMTS5 activity.

The online version contains supplementary material available at 10.1038/s41598-025-29549-3.