Background:The final rate-limiting step in pyrimidine synthesis is the conversion of UTP to CTP which is catalyzed by cytidine triphosphate synthase 1 (CTPS1) or CTPS2. A hypomorphic mutation in the CTPS1 gene has highlighted the essential and non-redundant role of CTPS1 in T and B lymphocyte proliferation1. These patients exhibit no effects on non-hematopoietic tissues. Thus, selective inhibition of CTPS1 represents a novel targeted approach to dampen pathological T- and B-cell lympho-proliferation. STP938 is an orally bioavailable, small molecular weight, selective inhibitor of CTPS1 developed by Step Pharma.Objectives:To demonstrate the in vitro effects of CTPS1 inhibition on T and B cell proliferation and the therapeutic potential of STP938 using in vivo models of disease.Methods:The in vitro anti-proliferative activity of STP938 was investigated using cell lines and primary human PBMCs. STP938 was assessed in vivo using the DTH-KLH rat model and the mouse collagen-induced arthritis (CIA) model. For the KLH-DTH model, Lewis rats were immunized with KLH, a week later, challenged locally at the ear with KLH antigen, ear swelling was assessed after 24 hours. Blood samples were collected for detection of KLH-specific IgG levels at day 8. STP938 was given orally one-hour prior to immunization and then b.i.d. for 7 days. For the CIA model, DBA-1 mice were immunized with Collagen type II and complete Freund’s adjuvant and received a booster immunization three weeks later. STP938 was administered to mice developing signs of arthritis from Day 28 to 45 orally daily b.i.d.Results:STP938 inhibited in vitro proliferation of HEKwt but not HEK-CTPS1KO cells as well as Jurkat and human PBMCs. STP938 demonstrated a significant and dose-dependent inhibition of KLH-specific T and B cell responses in vivo. STP938 significantly reduced the disease severity in the CIA model in a dose-dependent manner as determined by clinical and histopathological readouts.Conclusion:Our preliminary in vitro and in vivo results indicate that inhibition of CTPS1 specifically blocks proliferation of cells derived from the lymphocyte lineage and reduces the T cell driven inflammatory response. These data highlight the therapeutical potential of STP938 in treating patients with autoimmune diseases such as rheumatoid arthritis.References:[1]Martin et al, JCI Insight. 2020, 12;5(5):133880Disclosure of Interests:Hélène ASNAGLI Employee of: Step Pharma, Andrew Novak: None declared, Louise Birch Shareholder of: Step Pharma, Rebecca Lane: None declared, Norbert Minet Employee of: employee as Ph D student under CIFRE grant, David Laughton: None declared, Pascal George Shareholder of: Step Pharma, Geoffroy de Ribains Shareholder of: as former employee of Step Pharma, Employee of: former employee of Step Pharma, Sylvain Latour: None declared, Alain Fischer: None declared, Tim Bourne Shareholder of: UCB, Step Pharma, Sitryx Therapeutics, Consultant of: a range of biotech companies, Employee of: former employee of Step Pharma and Sitryx Therapeutics, Andrew Parker Employee of: Step Pharma
Ochratoxin A Induces Oxidative Stress in HepG2 Cells by Impairing the Gene Expression of Antioxidant Enzymes
