RESUMEN
Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias Hematológicas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Pirimidinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Dihidroorotato Deshidrogenasa , Genómica/métodos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/patología , Humanos , Estadificación de Neoplasias , Proteómica/métodosRESUMEN
The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
Asunto(s)
Actinobacteria/genética , Antivirales/farmacología , Genoma Bacteriano , Macrólidos/farmacología , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína 1A de Unión a Tacrolimus/química , Proteína 1A de Unión a Tacrolimus/metabolismo , Actinobacteria/metabolismo , Secuencia de Aminoácidos , Antivirales/química , Antivirales/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Calcineurina/genética , Calcineurina/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Evolución Molecular , Células HEK293 , Humanos , Macrólidos/química , Macrólidos/metabolismo , Modelos Moleculares , Conformación Proteica , Homología de Secuencia , Sirolimus/química , Sirolimus/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
We describe the first definitive case of a fibrous dysplastic neoplasm in a Neandertal rib (120.71) from the site of Krapina in present-day Croatia. The tumor predates other evidence for these kinds of tumor by well over 100,000 years. Tumors of any sort are a rare occurrence in recent archaeological periods or in living primates, but especially in the human fossil record. Several studies have surveyed bone diseases in past human populations and living primates and fibrous dysplasias occur in a low incidence. Within the class of bone tumors of the rib, fibrous dysplasia is present in living humans at a higher frequency than other bone tumors. The bony features leading to our diagnosis are described in detail. In living humans effects of the neoplasm present a broad spectrum of symptoms, from asymptomatic to debilitating. Given the incomplete nature of this rib and the lack of associated skeletal elements, we resist commenting on the health effects the tumor had on the individual. Yet, the occurrence of this neoplasm shows that at least one Neandertal suffered a common bone tumor found in modern humans.
Asunto(s)
Displasia Fibrosa Ósea/diagnóstico por imagen , Hombre de Neandertal , Animales , Croacia , Displasia Fibrosa Ósea/patología , Fósiles , Costillas/diagnóstico por imagen , Costillas/patología , Microtomografía por Rayos XRESUMEN
With its location on a river with easy access to the sea, its central placement between the English speaking colonies to the north and south and its trading connections with the western frontier, there were many reasons Philadelphia became one of the most important towns of prerevolutionary America. In the early 1770s, it was the site of the first meeting organized to deal with the perceived inequities of the British government toward the colonies. It was where Thomas Jefferson wrote much of the Declaration of Independence, whose soaring statements reflecting the Age of Enlightenment spoke of the equality of all men. It was to this debate, centered on just who was included in this declaration that the origins of physical anthropology in America can be traced. Notable men in the early phases of this disputation included Samuel Stanhope Smith and especially Samuel George Morton, considered the founder of American physical anthropology. The American School of Anthropology, which argued for the polygenic origins of human races was substantially founded on Morton's work. Recent accusations that Morton manipulated data to support his racist views would appear unfounded. The publication of The Origin of Species in 1859 and the issuing of the Emancipation Proclamation in 1862-63 effectively ended the earlier debates. By the time of the American Civil War, 1861-65, physical anthropology was beginning to explore other topics including growth and development and anthropometry.
Asunto(s)
Antropología Física/historia , Historia del Siglo XVIII , Historia del Siglo XIX , Humanos , Philadelphia , Cráneo/anatomía & histologíaRESUMEN
Human biologic evolution involves a compromise between the physical adaptations for bipedalism with effects on birthing success and the much later increases in encephalization of our species. Much of what comes to define life history parameters like gestation length, and brain and birth weight in our species is best understood from this evolutionary perspective. Human populations have been dealing with the obstetric dilemma for many hundreds of thousands of years and modern biomedicine, using techniques like cesarean sections, has alleviated, but not eliminated, birthing as a "scar" of human evolution. If women begin to demand access to universal cesarean delivery, what will the outcome be for the future of human evolution? We can only speculate on the social, biologic, and demographic costs of this transition.