RESUMEN
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.
RESUMEN
Cationic dendritic amphiphiles were prepared through the linkage of interesting hydrophobic molecules such as cholesterol or vitamin E to the focal point of carbosilane dendrons. These new dendritic systems self-assembled in saline, producing micellar aggregates with hydrodynamic diameters ranging from 6.5 to 9.2 nm, and critical micelle concentrations of approximately 5 and 10 µM for second- and third-generation systems, respectively. The assemblies were able to encapsulate drugs of different charges (anionic, neutral, and cationic). Surprisingly, a 92% encapsulation efficiency for diclofenac was achieved in micelles prepared from second-generation dendrons. Toxicity measurements on peripheral blood mononuclear cells indicated different behavior depending on the generation, corresponding to the micellar regime. In contrast to the third-generation system, the second-generation system was non-toxic up to 20 µM, opening a window for its use in a micellar regimen, thereby operating as a drug delivery system for different biomedical applications.
RESUMEN
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.
Asunto(s)
Cocaína , Enfermedad de Parkinson , Animales , Compuestos de Bifenilo , Dopamina/metabolismo , Dopaminérgicos , Agonistas de Dopamina/farmacología , Humanos , Indazoles , Levodopa , Ligandos , Ratones , Nitrofuranos , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistasRESUMEN
Modulation of interactome networks, essentially protein-protein interactions (PPIs), might represent valuable therapeutic approaches to different pathological conditions. Since a high percentage of PPIs are mediated by α-helical structures at the interacting surface, the development of compounds able to reproduce the amino acid side-chain organization of α-helices (e.g. stabilized α-helix peptides and ß-derivatives, proteomimetics, and α-helix small-molecule mimetics) focuses the attention of different research groups. This appraisal describes the recent progress in the non-peptide α-helix mimetics field, which has evolved from single-face to multi-face reproducing compounds and from oligomeric to monomeric scaffolds able to bear different substituents in similar spatial dispositions as the side-chains in canonical helices. Grouped by chemical structures, the review contemplates terphenyl-like molecules, oligobenzamides and heterocyclic analogues, benzamide-amino acid conjugates and non-oligomeric small-molecules mimetics, among others, and their effectiveness to stabilize/disrupt therapeutically relevant 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 in clinical trials, are also remarked. The discovery of a continuously increasing number of new disease-relevant PPIs could offer future opportunities for these and other forthcoming α-helix mimetics.
Asunto(s)
Aminoácidos/química , Benzamidas/química , Compuestos Heterocíclicos/química , Proteínas Proto-Oncogénicas c-mdm2/química , Bibliotecas de Moléculas Pequeñas/química , Humanos , Estructura Molecular , Peptidomiméticos , Unión ProteicaRESUMEN
Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras-guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switchâ II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need.