Vimentin

Clinical Resources

Small Molecule

Through extensive studies on mechanism of action, target engagement and biological actions in vitro and in vivo, R491 is a first-in-class compound that binds specifically to vimentin.

● Specific binding site
● Potent therapeutic effect
● Rapid and reversible mechanisms of action
● Wide safety window

Fibrosis

Fibrosis is the formation of fibrous connective tissues in response to injury, and its continued activation is highly detrimental. Fibrotic diseases cause over 800,000 deaths per year worldwide, accounting for approximately 45% of total deaths. The incidence of fibrotic disease and subsequently, the number of fibrosis-related deaths will increase substantially with the problem of a continued ageing world population.

Fibrotic changes can occur in various vascular disorders, including cardiac disease, cerebral disease, and peripheral vascular disease, as well as in all the main tissues and organ systems, including the skin, kidney, lung, and liver. In these epithelial organs, the replacement of normal functional units of cells with collagen-rich scar tissue and the architectural distortion caused by scar retraction are major factors in progressive loss of organ function and eventual failure.

Although fibrosis is a well-recognized cause of morbidity and mortality in a range of disease states, there are currently no viable therapies to reverse the effects of chronic fibrosis.

Coronavirus Disease 2019 (Covid-19)

SARS-CoV-2 was characterized as a beta-coronavirus and recognized as the seventh discrete coronavirus species capable of causing human disease. The disease caused by the virus was officially named coronavirus disease 2019 (Covid-19) by WHO. According to the WHO, as of October 4, 2020, more than 34.8 million laboratory-confirmed cases of Covid-19 had been diagnosed and reported worldwide. Also, as of this date, WHO had confirmed more than one million deaths from Covid-19 worldwide.

Person-to-person transmission of SARS-CoV-2 is primarily via inhalation of suspended respiratory droplets, i.e., secretions (> 5 mcm) generated when an infected individual coughs, sneezes or speaks, or through direct contact with an infected patient.

As the number of people affected by the Covid-19 pandemic steadily multiplying and with a lack of virus-specific therapies, various host-directed therapies are investigated to treat the most seriously ill patients, such as nutritional interventions, immunoenhancing agents, convalescent plasma, and traditional Chinese medicine.

Figures from Sci Transl Med. 2013 Jan 9;5(167):167sr1. and Nat Med. 2020 Jul;26(7):1017-1032.

Changing the Dynamic Nature of Vimentin

As a most widely distributed intermediate filament protein, vimentin plays an important role in stabilizing intracellular architecture. At cellular level, vimentin is implicated in cell proliferation, stiffness, adhesion, migration, differentiation, senescence and apoptosis, which is taken advantage of by pathogenic cells in diseases. Vimentin also functions in inflammation and immune responses, as well as in the epithelial to mesenchymal transition (EMT). In addition, vimentin has been shown to be implicated in the processes of virus fusion, replication, assembly, binding and entry.

Thus, vimentin is proposed as a potential therapeutic target in fibrosis diseases, virus infection and cancer treatment.

The figure from BMJ Open Resp Res 2020;7:e000623.

R491 is a small molecule binding to vimentin to reduce the flexibility of vimentin intermediate filament, accompanied by:

● Direct activation of Treg cells, which suppresses overreacted immune system.
● Blockade of cancer exosome release, which hinders the communication of cancer cells with normal cells and impedes the formation and the maintenance of tumor microenvironment.
● Inhibition of endocytosis and endosomal trafficking, which interrupts the entry, trafficking, and egress of viruses, such as SARS-CoV2, that use these cellular processes for successful infection.
● Inactivation of fibroblasts, reduction of collagen production, and stimulation of reabsorption of already-deposited collagen, which address multiple pathogenic processes of tissue fibrosis.

IND Filing

IND-enabling studies of R491 including GLP toxicity studies in rats and dogs have been completed. IND filing and Phase 1 clinical trial are being prepared.

Patents have been granted in the US and Russia, pending in China, Japan, Europe, South Korea, Canada, Mexico, Brazil, Australia, India, Singapore and HK.