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

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.This work was supported by grants PID2022-138797OB-I00, PGC2018-096049-B-I00 and PID2021-126663NB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”; grant PID2019-106279RB-I00 funded by MCIN/AEI/10.13039/501100011033; grant PDC2022-133488-I00 funded by MCIN/AEI/10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR”; grants PI21/00191 and CP19/00140 funded by Instituto de Salud Carlos III; CNIO agreements 2017-2020, 2020-2023 funded by Foundation CRIS contra el Cancer; grants BIO-198 and P18-FR-3487 funded by Junta de Andalucía; VI PPIT program funded by Universidad de Sevilla; and by Ramón Areces Foundation. The authors acknowledge technological support from NMR, mass spectrometry and elemental analysis CAIs (Complutense University of Madrid), Biointeractomicts Platform (cicCartuja, Seville), and the Services at CITIUS (University of Seville). S.A., A.S.-M., I.A.-A. and R.L.G.-A. are grateful to Ministerio de Ciencia e Innovación and Complutense University of Madrid for predoctoral fellowships; M.V.-E. to European Union’s Horizon 2020 for Marie Sklodowska-Curie grant; and P.A.-G. to Fundación Española de Hematología y Hemoterapia for grant. The authors thank Dr. Adrián Velázquez-Campoy at the University of Saragossa for helping in fitting ITC analysis and Prof. Miguel A. De la Rosa at the University of Seville for critical reading of the manuscript.Peer reviewe

2-(Fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson’s Disease

Tolerance development caused by dopamine replacement with L-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4′- (S-methanesulfonimidoyl)-1,1′-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances L-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson’s disease

Nuevas moléculas inspiradas en metabolitos de la microbiota y su estudio fenotípico en cáncer

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica, leída el 19-07-2019In the past three decades, target-based drug discovery (TDD) has been the dominant approach to drug discovery. However, in recent years, there has been a renewed interest in phenotypic drug discovery (PDD) approaches, which allow to identify biologically active molecules in a physiologically relevant system, without needing to know the target protein a priori. In the present medicinal chemistry project, a PDD program will be addressed to identify new drug candidates. Human microbiota is a complex ecosystem of symbiotic microorganisms that play an important role in human health and disease. The crosstalk between the host and its microbiome occurs in part through the secretion of metabolites, which can regulate human proteins. Recent studies suggest the influence of the microbiota and its metabolites in several diseases, such as cancer, obesity, diabetes, immune system disorders, or neurological pathologies. In the context of cancer, various microbiota metabolites have been shown to play a major role in tumor protection. Therefore, these metabolites could represent an unexplored chemical space with important biological activities. In this work, we have developed new small molecules inspired on microbiota metabolites that could lead to novel therapeutic strategies for cancer treatment...En las últimas décadas, el descubrimiento de fármacos dirigidos a una diana terapéutica específica, target-based drug discovery (TDD), ha sido la estrategia predominante en la búsqueda de nuevos fármacos. Sin embargo, recientemente ha resurgido el interés por los programas basados en estudios fenotípicos, phenotypic drug dicovery (PDD), los cuales permiten identificar compuestos que inducen una respuesta biológica de interés sin la necesidad de conocer la diana molecular subyacente. Los ensayos fenotípicos proporcionan un enfoque menos sesgado para detectar moléculas capaces de regular una diana terapéutica y los compuestos identificados suelen tener un mayor impacto terapéutico in vivo. En este contexto, el presente proyecto de química médica se ha abordado mediante un programa de PDD enfocado al descubrimiento de nuevos fármacos antitumorales...Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEunpu

Evolution in non-peptide α-helix mimetics on the road to effective protein-protein interaction modulators

Modulation of interactome networks, essentially protein-protein interactions (PPIs), might representvaluable therapeutic approaches to different pathological conditions. Since a high percentage of PPIs aremediated bya-helical structures at the interacting surface, the development of compounds able toreproduce the amino acid side-chain organization ofa-helices (e.g. stabilizeda-helix peptides andb-derivatives, proteomimetics, anda-helix small-molecule mimetics) focuses the attention of differentresearch groups. This appraisal describes the recent progress in the non-peptidea-helix mimeticsfield,which has evolved from single-face to multi-face reproducing compounds and from oligomeric tomonomeric scaffolds able to bear different substituents in similar spatial dispositions as the side-chainsin canonical helices. Grouped by chemical structures, the review contemplates terphenyl-like molecules,oligobenzamides and heterocyclic analogues, benzamide-amino acid conjugates and non-oligomericsmall-molecules mimetics, among others, and their effectiveness to stabilize/disrupt therapeuticallyrelevant PPIs. The X-ray structures of a couple of oligomeric peptidomimetics and of some small-molecules complexed with the MDM2 protein, as well as the state of the art on their development inclinical trials, are also remarked. The discovery of a continuously increasing number of new disease-relevant PPIs could offer future opportunities for these and other forthcominga-helix mimetics.This research was funded by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU-FEDER), grantnumber RTI2018-097189-B-C22 to RGM, and CSIC grant numbers201880E109 to MMM and 2019E030 to RGM

SARS-CoV-2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still affecting people worldwide. Despite the good degree of immunological protection achieved through vaccination, there are still severe cases that require effective antivirals. In this sense, two specific pharmaceutical preparations have been marketed already, the RdRp polymerase inhibitor molnupiravir and the main viral protease (Mpro) inhibitor nirmaltrelvir (commercialized as Paxlovid, a combination with ritonavir). Nirmaltrelvir is a peptidomimetic acting as orally available, covalent and reversible inhibitor of SARS-CoV-2 Mpro. The success of this compound has revitalized the search for new peptide and peptidomimetic protease inhibitors. This Highlight collects some selected examples among those recently published in the field of SARS-CoV-2.We thank the CSIC (PIE-COVID-153, and PIT + Salud Global) for financial supportPeer reviewe

Spanish Lung Cancer Group SCAT trial: surgical audit to lymph node assessment based on IASLC recommendations

Background: The Spanish Customized Adjuvant Therapy (SCAT) trial assessed the role of individualized adjuvant therapy in clinical N0 incidental pN1 and/or N2 non-small cell lung cancer (NSCLC) completely resected. We assessed surgical topics with an in-depth analysis of quality of lymphadenectomy based on International Association for the Study of Lung Cancer (IASLC) recommendations.Methods: Patients with information about lymphadenectomy available were included (N=451). Prospectively collected data about tumor, type of resection, and postoperative morbidity and quality of lymph node dissection (LND) were retrospectively evaluated. Role of lymph node assessment on survival was analyzed using Kaplan-Meier curves, using regression models to identify prognostic factors.Results: In 33.7%, 17.7% and 49.9% of cases, regions 7, 10 and 11 respectively were not assessed. In 21.1% of patients, less than three lymph node regions were biopsied, while in 19.6% of patients less than six lymph nodes were assessed. In 53,4% of patients only one N1 region was evaluated. From patients with positive N2, 8.9% had no N1 regions biopsied. Twenty-nine percent of patients with at least one N2 lymph node resected shown the highest region involved. Thirty-day postoperative mortality was unknown. Five-year overall survival (OS) was 61.7% (95% CI: 55.4-67.4%), 51.5% (95% CI: 39.2-62.4%) and 42.3% (95% CI: 32.1-52.2%) for patients with N1, N2 and N1+N2 disease, respectively (

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

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

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

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

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

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