Abstract 4273: Discovery of first in class, polyphenolic inhibitors of CKAP4 and their antitumor activity in ovarian and endometrial cancer

While some plant-derived polyphenolic compounds exhibit anticancer activity, their complex mechanism of action is generally hindering the efforts to produce clinically useful derivatives. Here we present several compounds that are, to the best of our knowledge, the first known inhibitors of cytoskeleton associated protein 4 (CKAP4) a transmembrane protein associated with resilient forms of cancer. Since CKAP4 is overexpressed in ovarian cancer the compounds were evaluated in the experimental models below as proof of concept. Target deconvolution using CETSA was followed by spectral shift binding, TRIC and ITC validation. In vitro studies assessed anti-proliferative activity (ATPLite, Revvity), with Oncolines Profiler analysis comparing the IC50 fingerprints with those of 213 pre-profiled reference drugs. Bioprinted human tissue organoids tested the efficacy of the new chemical entities. Tumor microenvironment characterization was performed using immunofluorescence imaging.From our proprietary physical library of 400 new chemical entities SND 106, 108, 562, 581, 584 and 586 were selected based on their strong binding to CKAP4. They were highly active in the ovarian and endometrial cell lines: PA-1, ES-2, AN3-CA, OVCAR-3 with IC50s in the low nanomolar range. Furthermore, the results of the organoid assays showed a significantly improved efficacy of the new compounds compared with the standard of care drug carboplatin.Novel, first-in-class small molecules inhibitors of CKAP4 were discovered, showing strong antitumor activity in ovarian and endometrial cancer. Future studies will determine whether they can be developed into new drugs. Citation Format: Eugenio Gaudio, Viktor Ivasishin, Paulina Biniecka, Christian Kleusch, Cosimo Kropp, Benjamin Zimmer, Kamilla Pawlicka, Helena Almqvist, Alexey Chernobrovkin, Janneke Melis, Guido Zaman, Dan F. Stoicescu. Discovery of first in class, polyphenolic inhibitors of CKAP4 and their antitumor activity in ovarian and endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4273.