Design and synthesis of CD70 inhibitors: a potential way for the treatment of ulcerative colitis

Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis (UC), are chronic disorders of the gastrointestinal tract characterized by an abnormal immune response driven by mucosal T cells. Current treatments depend on the disease stage, but present contraindications and side effects. 1 The CD70/CD27 co-stimulatory pathway recently emerged as a new potential therapeutic target for the treatment of UC. 2 Compared to intestinal organoids generated from pediatric non-UC patients, it was observed that UC-patients derived organoids present significantly high levels of CD70, a type II transmembrane glycoprotein of the TNF superfamily, whose overexpression is related to an overproduction of pro-inflammatory cytokines. Disrupting the CD70/CD27 interaction by CD70 inhibition should reduce the inflammatory responses and provide beneficial effects to the disease. Relying on the known crystal structure of human CD27 in complex with human CD70, 3 a virtual screening of small molecules was performed, leading to the identification of hit compounds 1-3 (Figure 1). Figure 1. Identified hit compounds and proposed optimization for hit compound 3 Commercially available compound 3 showed a CD70 binding affinity of 98 μM (measured by MST) and was selected as template. Several analogues of compound 3 were then designed by computational studies and synthesized. The obtained compounds are currently undergoing MST evaluation to assess their binding affinity to the target as well as their anti-inflammatory properties. References 1. Eguzkiñe Diez-Martin et al., Int. J. Mol. Sci. 2024, 25, 7062 2. J. Denoeud et al., Leukoc. Biol. 2010, 89, 195-203 3. Weifeng Liu et al., J. Biol. Chem. 2021, 297, 101102