Abstract 2471: Novel Tetrazolo-pyridazine based MACC1 inhibitors are promising for anti-metastatic therapy

Abstract

Cancer metastasis is the most lethal attribute of cancer, frequently caused by insufficient therapies and limited therapy options. Novel compounds able to interfere with metastasis formation are therefore of tremendous interest. Colorectal Cancer (CRC) is the third most prevalent and second most lethal cancer worldwide. In CRC, metastasis formation is linked to poor patient survival and treatment failure. Up to 90% of CRC related deaths are attributed to metastasis formation. Identification of causative drivers of metastasis represents the basis for effective anti-metastatic therapy. Our lab newly identified the gene MACC1 (Metastasis Associated in Colon Cancer 1). MACC1 is a key causal molecule for tumor progression and metastasis formation. It is a stage independent prognostic marker, predicting the onset of metastasis in stages I, II and III, based on tumor tissue analyses or blood-based tests. MACC1 promotes several cancer hallmark capabilities, providing cells with a malignant phenotype. Further, MACC1 has been established as a prognostic and predictive biomarker for metastasis in CRC and more than 20 other solid cancer entities. We therefore searched for novel compounds targeting MACC1 transcription. A high-throughput screen with more than 118,500 compounds (EMBL, Heidelberg), employing CRC cells stably transfected with a MACC1 promoter-luciferase reporter construct, revealed a Tetrazolo-pyridazine based compound as a promising lead for effective inhibition of MACC1 expression. We demonstrated that several SAR and MedChem-generated analogues of our lead compound effectively inhibit MACC1 gene expression and MACC1 driven cancer cell motility in vitro in CRC and cross entity cell lines. Further, they inhibit MACC1-induced tumor progression and metastasis in vivo in CRC xenograft models in mice. Moreover, ADMET studies were conducted, confirming our compounds are likely to be orally active drug with high stability in human plasma, low plasma protein binding and great permeability with neglectable efflux in MDR1-MDCKII assay. Through RNA-sequencing and subsequent gene set enrichment analysis a hypothesis on the mode of action was formed. An immune pathway has been identified as the most promising signaling pathway targeted by these compounds, which is currently explored through knock down and signaling studies. Taken together, this novel class of small molecules represents promising candidates for anti-metastatic therapy in CRC and other solid cancer patients in a personalized medicine setting. Citation Format: Yan Shixian, Paul Schöpe, Joe Lewis, Kerstin Putzker, Ulrike Uhrig, Edgar Specker, Jens von Kries, Hector E. Sanchez-Ibarra, Anke Unger, Mia Zischinsky, Bert Klebl, Peter Lindemann, Wolfgang Walther, Marc Nazaré, Dennis Kobelt, Ulrike Stein. Novel Tetrazolo-pyridazine based MACC1 inhibitors are promising for anti-metastatic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2471.