Discovery of 1,2,3triazolo4,5-dpyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Publication date: Available online 16 December 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Zhenzhen Liu, Taoqian Zhao, Zhonghua Li, Kai Sun, Yundong Fu, Ting Cheng, Jimin Guo, Bin Yu, Xiaojing Shi, Hongmin LiuAbstractUbiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC50=1.10±0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1 (IC50>100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deub...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research

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This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free." Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease https://www.fightaging.org/archives/2020/01/commentary-on-recent-evidence-for-cognitive-decline-to-precede-amyloid-aggregation-in-alzheimers-disease/ I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, the anti-cancer mechanisms of 4-XL-PPD were investigated. The results showed that compound 4-XL-PPD resulted in a concentration-dependent inhibition of cells viability in gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1). In BGC-803 cancer cells, 4-XL-PPD triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Meantime, 4-XL-PPD effectively suppressed the migratory and invasive capabilities of BGC-803 cancer cell and inhibited the expression leve...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
In this study, the anti-cancer mechanisms of 4-XL-PPD were investigated. The results showed that compound 4-XL-PPD resulted in a concentration-dependent inhibition of cells viability in gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1). In BGC-803 cancer cells, 4-XL-PPD triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Meantime, 4-XL-PPD effectively suppressed the migratory and invasive capabilities of BGC-803 cancer cell and inhibited the expression leve...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
Publication date: July 2019Source: Biomedicine &Pharmacotherapy, Volume 115Author(s): Syedeh Elham Norollahi, Fariborz Mansour-Ghanaei, Farahnaz Joukar, Shervin Ghadarjani, Kourosh Mojtahedi, Kaveh Gharaei Nejad, Hossein Hemmati, Faeze Gharibpoor, Roya Khaksar, Ali Akbar SamadaniAbstractCancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and ...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
Abstract Cancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and chemotherapy. Correspondingly, gastric cancer (GC) as a very serious type in cancer mortality in the world, has received a deep attention in molecular therapy recently. Besides the main characteristics of CSCs like differentiation, epithelial mesenchymal transition, self-re...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
Conclusion MTDH is pro-oncogenic factor playing multifaceted and diverse roles in cancer progression. Its association and central role in regulating signaling pathways such a MAPK, wnt/β-catenin, PI3K/AkT, NF-κβ pathways in various cancers shows that it plays a vital role in metastasis. MTDH contribution to chemo and radiotherapy resistance provides a new direction for the development of anticancer therapeutics. Multiple mechanisms converge to promote expression of MTDH in cancers. Further studies are therefore warranted to determine whether the elevated MTDH expression has prognostic value for development...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: We found a highly reliable FI network, which revealed LIFR, PIK3R1, and MMP12 as novel prognostic biomarker candidates for GBC. These findings could accelerate biomarker discovery and therapeutic development in this cancer. Introduction Gallbladder cancer (GBC), the sixth most common gastrointestinal cancer, is an uncommon but challenging disease. Its incidence has recently increased highly worldwide (1). The risk factors for GBC include sex, aging, obesity, chronic cholecystitis, and cholelithiasis (2, 3). Because of the lack of an effective early diagnostic method, the disease often is not diagnosed ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Michal Yalon1†, Amos Toren1,2†, Dina Jabarin2, Edna Fadida3, Shlomi Constantini3 and Ruty Mehrian-Shai1* 1Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel 2The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 3Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv-Sourasky Medical Center, Tel Aviv, Israel Pediatric brain tumors are the most common solid tumor type and the leading cause of cancer-related death in children. The immune system plays an important r...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions Several model systems are now available to characterize the MSC-tumour interplay in the TME. These offer early promise in establishing robust preclinical platforms for the identification of crucial molecular pathways and for the assessment of clinical efficacy of novel drugs to inhibit cancer development and progression. However, selection of the right model for a given study should be shaped on the purpose, and should also consider fixed biological, biochemical, and biophysical parameters according to the specific tumour type. Finally, in order to get reliable and useful results to be translated to the clinic...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions This review describes how leukocyte-heparanase can be a double-edged sword in tumor progression; it can enhance tumor immune surveillance and tumor cell clearance, but also promote tumor survival and growth. We also discuss the potential of using heparanase in leukocyte therapies against tumors, and the effects of heparanase inhibitors on tumor progression and immunity. We are just beginning to understand the influence of heparanase on a pro/anti-tumor immune response, and there are still many questions to answer. How do the pro/anti-tumorigenic effects of heparanase differ across different cancer types? Does...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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