Creating RS5614 and its Property

Based on the structure of the human PAI-1 molecule, we obtained 96 PAI-1 inhibitory candidate compounds from a library of approximately 2 million virtual compounds using computer engineering. We have synthesized more than 1,400 new inhibitory compounds over the past 10 years, and evaluated the PAI-1 inhibitory activities and safeties, resulting in identification of RS5275, a compound that can be orally administered with excellent safety. We further created four clinical candidate compounds, RS5441, RS5484, RS5509 and RS5614 through further chemical synthesis and screening. Among them, we finally selected RS5614, which has the highest efficacy and safety profile, as our clinical candidate compound. In fact, RS5614 has passed all the non-clinical safety studies required for clinical trials and marketing as a pharmaceutical product. RS5614 has been administered to over 200 subjects (healthy volunteer, chronic myeloid leukemia, novel coronavirus lung injury, and malignant melanoma) to date, and RS5614 has been administered for one year in chronic myeloid leukemia. No serious adverse events have been reported in the studies, and therefore RS5614 can be a safe drug.

PAI-1 promotes the aging of the organisms through its effect on cellular senescence, so drugs that inhibit the action of PAI-1 can improve the main symptoms of aging.

We have conducted research on “PAI-1 and Aging” in collaboration with Northwestern University in the United States. Cells of living organisms cannot proliferate without limit due to cellular senescence. This phenomenon involves the p53 gene, which functions as “the brake” on cell proliferation and promotes cellular senescence. Furthermore, senescent cells have extremely high expression of PAI-1 in addition to excessive p53. In fact, it has become clear that the phenomenon of cellular senescence can be inhibited by suppressing either p53 or PAI-1. It was reported that PAI-1 expression is high not only in cells, but also in aged tissues and individuals (klotho mice, a model of premature aging; and Werner’s syndrome patients with premature aging). In the klotho mouse model of aging, the inhibition of PAI-1 expression and activity can ameliorate all the main symptoms of aging. PAI-1 expression is extremely high in cancer, atherosclerosis, chronic obstructive pulmonary disease, diabetes, kidney disease, and Alzheimer’s disease, all of which develop with aging, and treatment with PAI-1 inhibitors can also markedly improve pathological conditions in these animal disease models.

With aging, diseases such as cancer, vascular (atherosclerosis), pulmonary (emphysema, chronic obstructive pulmonary disease), metabolic (diabetes, obesity), renal (chronic kidney disease), bone and joint (osteoporosis, osteoarthritis), and brain (cerebrovascular disease, Alzheimer’s disease, and dementia) develop. Interestingly, PAI-1 expression is extremely high in tissues affected by these diseases. Furthermore, PAI-1 inhibitor administration to animal models of these diseases has been shown to markedly improve their pathologies. Thus, interesting facts are coming to light on the important connection between PAI-1 and aging.

Recently, it is reported that senescent cells express PD-L1, a protein that acts as “the brake” for immunity (immune checkpoint molecule) and allows themselves to escape immune attack. The first immune checkpoint inhibitor anti-PD-1 antibody (nivolumab, trade name: Opdivo) was developed as a new treatment for cancer (cancer immunotherapy) against the immune checkpoint molecule PD-1 that was discovered by Dr. Tasuku Honjo and his colleagues at Kyoto University (the Nobel Prize was awarded to Dr. Tasuku Honjo in 2018). When anti-PD-1 antibody was administered to model mice of aging and lifestyle diseases, the activated immune system eliminates senescent cells, improving the aging process of organs and tissues and lifestyle diseases.

We discovered that PAI-1 is involved in the expression of immune checkpoint molecules in cancer cells and promotes the proliferation of cancer cells, and that therefore the PAI-1 inhibitor functions as an immune checkpoint inhibitor. Thus, PAI-1 promotes cancer and aging, and our PAI-1 inhibitor is effective against cancer and other aging-related diseases.

In the past, many pharmaceutical companies and bio-ventures, including major Japanese and foreign companies, have worked on the development of small molecule PAI-1 inhibitors, and several drugs were reported to be effective in animal models in mice and rats. However, all of them were discontinued at an early stage of development, and our compound is the only PAI-1 inhibitor in the clinical stage that can be orally administered.