RT Journal Article
T1 Cancer stem cell phenotype guided discovery of a microbiota inspired synthetic compound targeting NPM1 for leukemia
A1 Algar, Sergio
A1 Vázquez Villa, María Del Henar
A1 Aguilar Garrido, Pedro
A1 Navarro Aguadero, Miguel Ángel
A1 Velasco Estévez, María
A1 Sánchez Merino, Anabel
A1 Arribas Álvarez, Iván
A1 Paradela, Alberto
A1 Giner Arroyo, Rafael L.
A1 Tamargo Azpilicueta, Joaquín
A1 Díaz Moreno, Irene
A1 Gallardo, Miguel
A1 Martínez López, Joaquín
A1 López Rodríguez, María Luz
A1 Benhamú Salama, Bellinda
AB The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.
PB ACS Publications
SN 2691-3704
SN 2691-3704
YR 2024
FD 2024-02-09
LK https://hdl.handle.net/20.500.14352/109520
UL https://hdl.handle.net/20.500.14352/109520
LA eng
NO Algar S, Vázquez-Villa H, Aguilar-Garrido P, Navarro-Aguadero MÁ, Velasco-Estévez M, Sánchez-Merino A, Arribas-Álvarez I, Paradela A, Giner-Arroyo RL, Tamargo-Azpilicueta J, Díaz-Moreno I, Martínez-López J, Gallardo M, López-Rodríguez ML, Benhamú B. JACS Au. 2024 Feb 9;4(5):1786-1800
NO Ministerio de Ciencia e Innovación (España)
NO Instituto de Salud Carlos III
NO Universidad de Sevilla
NO Junta de Andalucía
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 10 jun 2026