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Matriptase inhibitor for utility in Osteoarthritis as disease modifying therapy

Dr Drew Rowan, Newcastle University; Dr Tim Chapman, LifeArc; Dr Lorna Duffy, Sygnature Discovery Ltd; Dr Prem Meghani, Sygnature Discovery Ltd



Osteoarthritis (OA) is a gradually progressive joint disease that is typically seen in middle-aged to elderly people. According to the American College of Rheumatology (ACR), OA is the most common cause of disability in the elderly (ACR, 2017). The most commonly affected joints are the knee, hip, hand, and spine. OA is characterized by breakdown of the cartilage, bony changes of the joints, deterioration of tendons and ligaments, and various degrees of inflammation of the joint lining. The prevalence of OA varies depending on the diagnostic definition used for the disease, as well as other factors (sex, age, geography). According to Arthritis Research UK, over 8 million people are affected by OA in the UK, and this condition is common in the developed world (Osteoarthritis is a disease that affects more than 70 million EU citizens).

OA incidence increases with age, is more common in women and has been linked with obesity which itself is an increasing problem. Once considered ‘wear & tear’, an inevitable consequence of ageing, research now reveals distinct biological pathways that contribute to OA pathogenesis, especially cartilage destruction, offering real potential to develop disease-modifying anti-OA drugs. Current licensed medications for OA are predominantly analgesics, NSAIDs and intraarticular corticosteroids that are not disease modifying and do not address tissue destruction.


This proposal aims to develop small molecule inhibitors for matriptase which would represent a first-in-class drug for OA that could potentially stop, or at least slow down, further cartilage damage in OA patients.

Matriptase is a strategically good target due to its position within the degradation cascade in OA cartilage where it serves as an initiator and inducer of MMPs. Furthermore, matriptase is absent from normal cartilage. Altogether, this makes matriptase a very promising target for OA with potentially disease-modifying activity.

Commercial Opportunity

The commercial opportunity exists for a company with an interest and focus in growing its pipeline in muscoskeletal disorders. Specifically, we are looking for a commercial partner with an interest in developing an intra-articular form of the lead molecule as the first product.

Development Status

The small molecules targeting matriptase have been identified and initial work in an in vivo mouse model of OA has shown protection from cartilage breakdown following administration of the hit compound by sub-cutaneous pump and intra-articular injection. Our latest highly potent derivatives are currently undergoing further testing in pre-clinical rodent models via intra-articular injection.

Patent Situation

A UK provisional application (1720145.0) has been filed describing a series of hit compounds and a family of derivatives.

Further Reading

Milner JM, Patel A, Davidson RK et al. (2010) Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum, 62(7):1955-66.


Matriptase inhibitor for utility in Osteoarthritis as disease modifying therapy

Mechanism of action of matriptase in AQ cartliage. Matriptase is expressed on chondrocytes 91) following abnormal loading of cartilage which also induces expression of PAR-2. Matriptase activity activates PAR-2 (2) which signals leading to the expression and secretion of proMPPs 93) some latent MMPs (eg, proMMP-3) are activated by matriptase (4) and MMP-3 and matriptase together then activate procollagenases. Active collagenases cleave collagen (5) which drives cartilage breakdown.