Since developed countries, including Japan, face super-aging population, aging has become an urgent issue not only medically but also socially. In our laboratory, we hope to elucidate cellular senescence at the molecular level, develop drugs to treat diseases related to “Aging” of tissues and individuals, and ultimately contribute to innovations to ameliorate human aging.
Cellular Senescence
Except for tumor cells, cells of living organisms cannot proliferate indefinitely due to a phenomenon called cellular senescence (replicative senescence). This phenomenon involves the shortening of telomere length of genomes, as well as cellular senescence factors such as p53. Senescent cells express extremely high levels of plasminogen activator inhibitor (PAI)-1 in addition to p53, and it has become clear that the phenomenon of cellular senescence can be inhibited by suppressing p53 and/or PAI-1.
Aging of Tissues and Individuals
It has been reported that PAI-1 expression is high not only in aged cells, but also in aged tissues and individuals (klotho mice and humans with Werner's syndrome, a well-known premature aging). In collaboration with Northwestern University in the U.S., we have shown that the main symptoms of aging can be ameliorated by inhibiting the expression or the activity of PAI-1 at the gene or protein level in klotho mice, the well-known model of aging.
Age-Related Diseases
With aging, various diseases develop, including cancer, vascular (atherosclerosis), pulmonary (emphysema, chronic obstructive pulmonary disease), metabolic (diabetes, obesity), renal (chronic kidney disease), bone and joint (osteoporosis, osteoarthritis), brain (cerebrovascular disease, Alzheimer's disease, and dementia). Interestingly, PAI-1 expression is extremely high in the tissues of these diseases, and it is now clear that the PAI-1 inhibitors can ameliorate the pathological conditions.
Epidemiological Study of a Long-Lived Family
Healthy aging among the Amish, a Christian sect living in the Midwestern United States, has been studied for more than a decade. In collaboration with Northwestern University in the U.S., we studied people from the Amish community and found that those without the PAI-1 gene (56 people) lived 10 years longer than those who had (165 people). We also found that those who were deficient were less susceptible to diseases such as diabetes. This fact was reported in the New York Times and many other newspapers in November 2017. This epidemiological study in humans confirms the results of experiments in cells and mice.
PAI-1 is a molecule required for the degradation of blood clots (called the fibrinolytic system), and a series of recent findings strongly suggest that it is involved in various diseases related to aging (senescence), making it a potential target for drug discovery. However, no drugs that can inhibit the activity of the human PAI-1 molecule have been applied to clinical practice. Our laboratory has been working on the development of PAI-1 inhibitors that have the potential to treat a series of age-related diseases.
Based on the crystal structure of the human PAI-1 molecule, we have obtained approximately 96 PAI-1 inhibitory candidate compounds from exploring a library of approximately 2 million virtual compounds with computer engineering. In the process of screening more than 1,400 new inhibitory compounds synthesized over the past 10 years, using PAI-1 inhibitory activity (suppression of tissue plasminogen activator (tPA) inhibition by PAI-1) and inhibition of PAI-1/tPA complex formation as the indicators, and further evaluating their activity and safety, we discovered TM5614, a candidate compound for clinical development that can be orally administered and has excellent safety profile. TM5614 was shown to bind to the vitronectin binding site of PAI-1.
We synthesized and screened the analogues from the lead compound TM5275 to obtain four clinical candidate compounds, TM5441, TM5484, TM5509, and TM5614. Each of these compounds has its own unique characteristics, such as oral absorption and pharmacokinetics (tissue penetration), and can be useful for different indications.
In the past, many pharmaceutical and biotech companies, including major domestic and foreign companies, have tried to create small molecule PAI-1 inhibitors. Several drugs have shown efficacy in mouse and rat animal models, and Wyeth's (now Pfizer) product PAI-749 (diaplasinin) advanced to the clinical stage, but development was terminated after a Phase I clinical trial. To date, TM5275 from our laboratory is the only compound that shows drug efficacy in a monkey pathology model as reported in the peer-reviewed journal. It is a low molecular weight compound that is extremely well absorbed and therefore reaches sufficient blood concentrations when administered orally. TM5614 was finally discovered as the clinical candidate through screening of the compounds for efficacy, kinetics, safety, and physical properties. The entire development process, from discovery to GLP non-clinical safety studies, GMP synthesis and formulation, and investigator-initiated clinical trials, was all conducted in our laboratory.
While non-clinical studies suggest that TM5614 may be effective in a wide range of age-related diseases, clinical trials (investigator-initiated clinical trials) are currently underway in oncology, including chronic myeloid leukemia (CML: early and late phase II studies completed, phase III studies ongoing), malignant melanoma (melanoma: phase II studies completed), non-small cell lung cancer (phase II on going) and cutaneous angiosarcoma (phase II on going), and in respiratory diseases, including lung injury associated with novel coronavirus infection (early and late phase II studies completed), interstitial lung disease associated with systemic scleroderma (phase II study on going), and interstitial pneumonia caused by anticancer agents (non-clinical studies on going). TM5614 has been also studied in FGF23-related hypophosphatemia rickets in a clinical study. TM5441 is for the treatment of male pattern baldness (phase I trial in preparation).