Chaimae El Hadri

PC9 – Chaimae El Hadri

Ghent University, Ghent, Belgium

chaimae.elhadri@ugent.be

Targeting CtBP Mediated Oncogenic Transcriptional Activity With Structure Guided Ligand
El Hadri Chaimae^1,2,4, DeBacker Robin^3,4, Savvas Savvides^3,4, Steven Goossens^1,4, Serge Van Calenbergh^2,4 ¹ Unit for Translational Research in Oncology (UTRiO), Ghent University, Ghent, Belgium ² Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgiuma ³ Unit for Structural Biology, VIB Ghent University, Ghent, Belgium ⁴ Cancer Research Institute Ghent (CRIG), Ghent, Belgium
Abstract C-terminal Binding Proteins (CtBP1/2) are NADH-dependent transcriptional corepressors frequently overexpressed in cancer, where they drive epithelial mesenchymal transition (EMT) and repress tumor suppressor programs (CDH1, BRCA1)[1-2]. However, the interplay between their catalytic activity, oligomerization, and transcriptional function remains poorly understood. Here, we report the structure guided development of new CtBP inhibitors derived from 2-hydroxyimino 3-phenylpropanoic acid (HIPP)[3]. The most potent compounds display nanomolar inhibition of CtBP dehydrogenase activity (IC₅₀ ≈ 20 nM). Biophysical and structural studies (thermal shift, ITC, and X-ray crystallography) reveal high affinity binding and show that the enzymatic inhibition is coupled to perturbation of CtBP oligomerization, a key determinant of its transcriptional activity. In breast and ovarian cancer models, the ethyl esters of these compounds reduce viability (IC₅₀ ≈ 15 µM) and induce transcriptional reprogramming consistent with CtBP modulation. These results provide insight into the relationship between CtBP catalytic activity and transcriptional regulation, and support further exploration of CtBP as a therapeutic target.
References [1] Deng, Y.; et al. Transcriptional Down-Regulation of Brca1 and E-Cadherin by CtBP1 in Breast Cancer. Mol. Carcinog. 2012, 51, 500–507. [2] Blevins, M. A.; Huang, M.; Zhao, R. The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target. Mol. Cancer Ther. 2017, 16, 981–990. [3] Hilbert, B. J.; et al. Structure-Guided Design of a High Affinity Inhibitor to Human CtBP. ACS Chem. Biol. 2015, 10, 1118–1127.