Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

Center for Cancer Research Medical University of Vienna Vienna Austria

Chemistry and Biochemistry Department Université de Moncton Moncton New Brunswick Canada

Department of Biological Sciences and Pathobiology Pharmacology and Toxicology University of Veterinary Medicine Vienna Vienna Austria

Department of Biosciences and Medical Biology Paris Lodron University of Salzburg Salzburg Austria

Department of Pathology Medical University of Vienna Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria; European Research Initiative on ALK Related Malignancies Cambridge UK

Department of Pathology Medical University of Vienna Vienna Austria; European Research Initiative on ALK Related Malignancies Core Lab 2 Medical University of Vienna Vienna Austria; Department of Molecular Biology Umeå University Umeå Sweden

Department of Physical Chemistry University of Debrecen Debrecen Hungary

European Research Initiative on ALK Related Malignancies Cambridge UK; Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK; Faculty of Medicine Masaryk University Brno Czech Republic

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