Tiantai ZHANG, PhD | Institute of Materia Medica, Chinese Academy of Medical Sciences; Lan SUN, MD; Chengjuan CHEN, PhD; Gaona SHI, PhD; Yu ZHOU, PhD; Yazi WEI PhD
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2024
Autoimmune diseases are a large category of diseases that cause tissue damage due to immune tolerance disorders of the body. Non-receptor tyrosine kinase (JAK) is a new target for the treatment of autoimmune diseases, which has been recognized after epoxidase in the last 40 years, and contains 4 subtypes. Due to non-selective inhibition, JAK inhibitors currently on the market have clinically critical problems such as serious opportunistic infections, anemia and other cardiovascular events, and many instructions of non-selective JAK inhibitors have been required by FDA to have a black box warning. Therefore, the R&D of selective JAK inhibitors reflects the necessity in terms of the severity and urgency of the disease, the shortage of therapeutic drugs, the novelty of the target, and overcoming the side effects of current non-selective JAK inhibitors. In the previous stage, we obtained a new selective JAK3 small molecule inhibitor of Z583 (Patent No. ZL201811078582.X in China and US11993603B2 in USA). The IC50 of Z583 was 0.10 nM, which was > 4500 times of the selectivity for JAK1, JAK2 and Tyk2 subtypes. Z583 showed a clear anti-RA effect on CIA model with the dose of 3mg/kg (p.o.). The toxicity evaluation showed no cardiotoxicity or mutagenicity, especially the acute toxicity test in rats given large doses for four consecutive weeks showed no routine blood and abnormal liver and kidney function, thus avoiding the occurrence of cardiovascular events such as anemia. Z583 is a highly selective JAK3 inhibitor with great potential for the treatment of autoimmune diseases.