Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

• DOI: 10.1021/jacsau.3c00682
• Publication Date: 2024-02-09T17:05:18Z
• Authors: Sergio Algar; Henar Vázquez-Villa; Pedro Aguilar-Gar...; Miguel Ángel Nava...; María Velasco-Est...; Anabel Sánchez-Me...; Iván Arribas-Álvarez; Alberto Paradela; Rafael L. Giner-A...; Joaquín Tamargo-A...; Irene Díaz-Moreno; Joaquín Martínez-...; Miguel Gallardo; María L. López-Ro...; Bellinda Benhamú
• Keywords: NPM1; Phenotypic screening; Synthetic Lethality; Chemical library

The human microbiota plays an important role in health and disease, through the secretion of metabolites that regulate key biological functions. We propose represent unexplored chemical space small drug-like molecules search new hits for drug discovery. Here, we describe generation a set complex chemotypes inspired on selected metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following primary screening CSC models, identified novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one most frequent mutations AML, NPM1-mutated AML recognized WHO as distinct hematopoietic malignancy. inhibits NPM1 expression, downregulates pathway associated with mutant C+, specifically recognizes C-end DNA-binding domain avoiding nucleus-cytoplasm translocation involved tumorological process. inhibitor triggers apoptosis cell lines cells from patients reduces tumor infiltration mouse model C+ mutation. disclosed phenotype-guided discovery UCM-13369, molecule confirms death induced inhibition represents promising therapeutic opportunity high-mortality disease.