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1.
Bioorg Chem ; 153: 107807, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39293304

RESUMEN

USP7 has been recognized as a potential target for the treatment of hematologic malignancies by stabilizing multiple cancer-relevant proteins. Nevertheless, drug-like USP7 inhibitors are still lacking. Herein, compound J21 (USP7 IC50: 41.35 ± 2.16 nM) was discovered based on the structure of L55 and its co-crystal complex with USP7. Additionally, J21 exhibited greater metabolic stability (T1/2: 1.25 h, Cmax: 394.1 ± 48.3 ng/mL, and AUC0-t: 597.8 ± 44.8 ng/mL∙h) compared to L55. These findings may further pave the way for the development of USP7 inhibitors for the treatment of hematologic malignancies.

2.
Arch Pharm (Weinheim) ; 357(4): e2300516, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38263717

RESUMEN

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.


Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Adulto , Simulación del Acoplamiento Molecular , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Detección Precoz del Cáncer , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Serina-Treonina Quinasas
3.
Molecules ; 27(6)2022 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-35335379

RESUMEN

Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 µM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 µM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma.


Asunto(s)
Antineoplásicos , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , Ratones Desnudos , Relación Estructura-Actividad
4.
Reprod Domest Anim ; 56(4): 629-641, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33492695

RESUMEN

The microenvironment in the seminiferous tubules of buffalo changes with age, which affects the self-renewal and growth of spermatogonial stem cells (SSCs) and the process of spermatogenesis, but the mechanism remains to be elucidated. RNA-seq was performed to compare the transcript profiles of pre-pubertal buffalo (PUB) and adult buffalo (ADU) seminiferous tubules. In total, 17,299 genes from PUB and ADU seminiferous tubules identified through RNA-seq, among which 12,271 were expressed in PUB and ADU seminiferous tubules, 4,027 were expressed in only ADU seminiferous tubules, and 956 were expressed in only PUB seminiferous tubules. Of the 17,299 genes, we identified 13,714 genes that had significant differences in expression levels between PUB and ADU through GO enrichment analysis. Among these genes, 5,342 were significantly upregulated and possibly related to the formation or identity of the surface antigen on SSCs during self-renewal; 7,832 genes were significantly downregulated, indicating that genes in PUB seminiferous tubules do not participate in the biological processes of sperm differentiation or formation in this phase compared with those in ADU seminiferous tubules. Subsequently, through the combination with KEGG analysis, we detected enrichment in a number of genes related to the development of spermatogonial stem cells, providing a reference for study of the development mechanism of buffalo spermatogonial stem cells in the future. In conclusion, our data provide detailed information on the mRNA transcriptomes in PUB and ADU seminiferous tubules, revealing the crucial factors involved in maintaining the microenvironment and providing a reference for further in vitro cultivation of SSCs.


Asunto(s)
Células Madre Germinales Adultas/fisiología , Búfalos/fisiología , Perfilación de la Expresión Génica/veterinaria , Maduración Sexual/fisiología , Animales , Regulación del Desarrollo de la Expresión Génica , Masculino , ARN Mensajero , Túbulos Seminíferos/citología , Túbulos Seminíferos/fisiología
5.
Reprod Fertil Dev ; 31(2): 386-394, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30309436

RESUMEN

The effects of acetyl-l-carnitine (ALC) supplementation during IVM on subsequently vitrified buffalo oocytes were evaluated, followed by determination of the mitochondrial DNA copy number, measurement of mitochondrial membrane potential (MMP) and identification of the lipid profile of oocyte membranes as markers of oocyte quality after vitrification. Supplementation with ALC during IVM significantly improved the rates of oocyte cleavage and morula and blastocyst formation, and increased MMP after vitrification compared with unsupplemented vitrified oocytes (P<0.05). Using a bidirectional orthogonal projection to latent structures discriminant analysis based on positive ion matrix-assisted laser desorption ionisation time-of-flight mass spectrometry data, five phospholipid ions (m/z 728.7 (phosphatidylcholine (PC) 32:3), 746.9 (PC 32:5), 760.6 (PC 34:1), 768.8 (PC P-36:3) and 782.6 (PC 36:4); P<0.05) were identified as significantly more abundant in fresh oocytes than in unsupplemented vitrified oocytes. Meanwhile, three phospholipid ions (m/z 734.6 (PC 32:0), 760.6 (PC 34:1), and 782.6 (PC 36:4); P<0.05) were more abundant in ALC-supplemented vitrified oocytes than in unsupplemented vitrified oocytes. Therefore, supplementation with ALC during IVM may improve buffalo oocyte quality after vitrification by enhancing mitochondrial function and altering the phospholipid composition of vitrified oocyte membranes.


Asunto(s)
Acetilcarnitina/farmacología , Desarrollo Embrionario/efectos de los fármacos , Lípidos de la Membrana/metabolismo , Mitocondrias/efectos de los fármacos , Oocitos/efectos de los fármacos , Animales , Búfalos , Criopreservación/métodos , Femenino , Técnicas de Maduración In Vitro de los Oocitos , Mitocondrias/metabolismo , Oocitos/metabolismo , Vitrificación
6.
Anim Reprod Sci ; 186: 44-51, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28982519

RESUMEN

Nanos2 belongs to the Nanos gene-coding family and is an important RNA-binding protein that has been shown to have essential roles in male germline stem cells development and self-renewal in mouse. However, little is known about Nanos2 in inchoate buffalo spermatogonia. Here, rapid-amplification of cDNA ends (RACE) was used to obtain the full-length buffalo Nanos2 sequence and bioinformatic analysis revealed a highly conserved Nanos2 sequence between buffalo and other mammalian species. Although Nanos2 was expressed in various tissues, the highest mRNA expression levels were found in testes tissue. Moreover, Nanos2 mRNA was abundant in fetal and pre-puberal testes but markedly decreased in the testes of adults. At the protein level, immunohistochemistry in pre-puberal testes revealed a pattern of NANOS2 expression similar to that for the undifferentiated type A spermatogonia marker PGP9.5. Furthermore, NANOS2 expression was low in adult testes and restricted to elongating spermatids. Altogether, our data suggest that Nanos2 is a potential preliminary molecular marker of inchoate buffalo spermatogonia, and may play an important role in buffalo spermatogonial stem cells (SSCs) development and self-renewal, as has been observed in other model animals.


Asunto(s)
Búfalos/genética , Marcadores Genéticos , Proteínas de Unión al ARN/genética , Espermatogonias/fisiología , Animales , Búfalos/crecimiento & desarrollo , Clonación Molecular , Biología Computacional , Regulación del Desarrollo de la Expresión Génica , Masculino , Maduración Sexual , Testículo/crecimiento & desarrollo
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