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https://www.readbyqxmd.com/read/29770817/the-dietary-compound-luteolin-inhibits-pancreatic-cancer-growth-by-targeting-bcl-2
#1
Zhimei Li, Yiyuan Zhang, Lixia Chen, Hua Li
Overexpression of the prosurvival protein BCL-2 contributes to malignant cell initiation, progression and resistance to treatment. Agents that function as its natural antagonists targeting BCL-2 must provide therapeutic benefit. In SW1990 pancreatic cancer cells, amplified BCL-2 was observed, which was believed to offer advantages for malignant cell survival and lead to poor patient outcome. Using structure-based virtual ligand screening, luteolin was found to be a natural small-molecule inhibitor of BCL-2, which exhibited dose-response proapoptosis activity in a BCL-2 dependent manner in vitro...
May 17, 2018: Food & Function
https://www.readbyqxmd.com/read/29767973/discovery-of-orally-bioavailable-quinoline-based-aldehyde-dehydrogenase-1a1-aldh1a1-inhibitors-with-potent-cellular-activity
#2
Shyh-Ming Yang, Natalia J Martinez, Adam Yasgar, Carina Danchik, Catrine Johansson, Yuhong Wang, Bolormaa Baljinnyam, Amy Q Wang, Xin Xu, Pranav Shah, Dorian Cheff, Xinran S Wang, Jacob Roth, Madhu Lal-Nag, James Edward Dunford, Udo C T Oppermann, Vasilis Vasiliou, Anton Simeonov, Ajit Jadhav, David J Maloney
Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g. ALDH1A1) are important biomarkers in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described...
May 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29706543/modulation-of-protein-interaction-states-through-the-cell-cycle
#3
Lingyun Dai, Tianyun Zhao, Xavier Bisteau, Wendi Sun, Nayana Prabhu, Yan Ting Lim, Radoslaw M Sobota, Philipp Kaldis, Pär Nordlund
Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of the biochemical processes determining cellular events. Using a proteome-wide implementation of the cellular thermal shift assay (CETSA) to study specific cell-cycle phases, we uncover changes of interaction states for more than 750 proteins during the cell cycle. Notably, many protein complexes are modulated in specific cell-cycle phases, reflecting their roles in processes such as DNA replication, chromatin remodeling, transcription, translation, and disintegration of the nuclear envelope...
April 21, 2018: Cell
https://www.readbyqxmd.com/read/29684682/identification-and-validation-nucleolin-as-a-target-of-curcumol-in-nasopharyngeal-carcinoma-cells
#4
Juan Wang, Jiacai Wu, Xumei Li, Haowei Liu, Jianli Qin, Zhun Bai, Bixia Chi, Chen Xu
Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells...
April 20, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29671171/new-use-for-cetsa-monitoring-innate-immune-receptor-stability-via-post-translational-modification-by-ogt
#5
Walter R Drake, Ching-Wen Hou, Natasha E Zachara, Catherine Leimkuhler Grimes
O-GlcNAcylation is a dynamic and functionally diverse post-translational modification shown to affect thousands of proteins, including the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (Nod2). Mutations of Nod2 (R702W, G908R and 1007 fs) are associated with Crohn's disease and have lower stabilities compared to wild type. Cycloheximide (CHX)-chase half-life assays have been used to show that O-GlcNAcylation increases the stability and response of both wild type and Crohn's variant Nod2, R702W...
April 18, 2018: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29617433/a-high-content-high-throughput-cellular-thermal-stability-assay-for-measuring-drug-target-engagement-in-living-cells
#6
Andrew J Massey
Determining and understanding drug target engagement is critical for drug discovery. This can be challenging within living cells as selective readouts are often unavailable. Here we describe a novel method for measuring target engagement in living cells based on the principle of altered protein thermal stabilization / destabilization in response to ligand binding. This assay (HCIF-CETSA) utilizes high content, high throughput single cell immunofluorescent detection to determine target protein levels following heating of adherent cells in a 96 well plate format...
2018: PloS One
https://www.readbyqxmd.com/read/29572378/mechanisms-of-resistance-to-ezh2-inhibitors-in-diffuse-large-b-cell-lymphomas
#7
Malik Bisserier, Narendra Wajapeyee
Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. In this study, we used this information for identifying the mechanisms of resistance to Enhancer of Zeste Homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We discovered that EZH2 inhibitor resistance DLBCL cells showed activation of the IGF-1R, MEK, and PI3K pathways. Constitutive activation of IGF-1R, MEK or PI3K pathways were sufficient to confer resistance to EZH2 inhibitors in DLBCL...
March 23, 2018: Blood
https://www.readbyqxmd.com/read/29433316/in-situ-target-engagement-studies-in-adherent-cells
#8
Hanna Axelsson, Helena Almqvist, Magdalena Otrocka, Michaela Vallin, Sara Lundqvist, Pia Hansson, Ulla Karlsson, Thomas Lundbäck, Brinton Seashore-Ludlow
A prerequisite for successful drugs is effective binding of the desired target protein in the complex environment of a living system. Drug-target engagement has typically been difficult to monitor in physiologically relevant models, and with current methods, especially, while maintaining spatial information. One recent technique for quantifying drug-target engagement is the cellular thermal shift assay (CETSA), in which ligand-induced protein stabilization is measured after a heat challenge. Here, we describe a CETSA protocol in live A431 cells for p38α (MAPK14), where remaining soluble protein is detected in situ, using high-content imaging in 384-well, microtiter plates...
April 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29343827/targeted-nudt5-inhibitors-block-hormone-signaling-in-breast-cancer-cells
#9
Brent D G Page, Nicholas C K Valerie, Roni H G Wright, Olov Wallner, Rebecka Isaksson, Megan Carter, Sean G Rudd, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Jofre Font-Mateu, Sabin Llona-Minguez, Pawel Baranczewski, Fredrik Jeppsson, Evert Homan, Helena Almqvist, Hanna Axelsson, Shruti Regmi, Anna-Lena Gustavsson, Thomas Lundbäck, Martin Scobie, Kia Strömberg, Pål Stenmark, Miguel Beato, Thomas Helleday
With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29317749/determining-direct-binders-of-the-androgen-receptor-using-a-high-throughput-cellular-thermal-shift-assay
#10
Joseph Shaw, Mathew Leveridge, Charlotta Norling, Jakob Karén, Daniel Martinez Molina, Daniel O'Neill, James E Dowling, Paul Davey, Suzanna Cowan, Michael Dabrowski, Martin Main, Davide Gianni
Androgen Receptor (AR) is a key driver in prostate cancer. Direct targeting of AR has valuable therapeutic potential. However, the lack of disease relevant cellular methodologies capable of discriminating between inhibitors that directly bind AR and those that instead act on AR co-regulators has made identification of novel antagonists challenging. The Cellular Thermal Shift Assay (CETSA) is a technology enabling confirmation of direct target engagement with label-free, endogenous protein in living cells. We report the development of the first high-throughput CETSA assay (CETSA HT) to identify direct AR binders in a prostate cancer cell line endogenously expressing AR...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29259156/dual-blockade-of-the-lipid-kinase-pip4ks-and-mitotic-pathways-leads-to-cancer-selective-lethality
#11
Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, See Cheng Shang, Noriaki Minami, Oltea Sampetrean, Hideyuki Saya, Dai Lingyun, Nayana Prabhu, Go Ka Diam, Radoslaw Sobota, Andreas Larsson, Pär Nordlund, Frank McCormick, Sujoy Ghosh, David M Epstein, Brian W Dymock, Sang Hyun Lee
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29247860/structure-activity-studies-on-n-substituted-tranylcypromine-derivatives-lead-to-selective-inhibitors-of-lysine-specific-demethylase-1-lsd1-and-potent-inducers-of-leukemic-cell-differentiation
#12
Johannes Schulz-Fincke, Mirjam Hau, Jessica Barth, Dina Robaa, Dominica Willmann, Andreas Kürner, Julian Haas, Gabriele Greve, Tinka Haydn, Simone Fulda, Michael Lübbert, Steffen Lüdeke, Tobias Berg, Wolfgang Sippl, Roland Schüle, Manfred Jung
FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals...
January 20, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29221173/farnesyl-phenolic-enantiomers-as-natural-mth1-inhibitors-from-ganoderma-sinense
#13
Ya Gao, Lihan Zhu, Jing Guo, Ting Yuan, Liqing Wang, Hua Li, Lixia Chen
Cancer cells are more addictive to MTH1 than normal cells because of their dysfunctional redox regulations. MTH1 plays an important role to maintain tumor cell survival, while it is not indispensable for the growth of normal cells. Farnesyl phenols having a coumaroyl substitution are rather uncommon in nature. Eight farnesyl phenolic compounds with such substituent moiety (1-8), including six new ones, ganosinensols E-J (1-6) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense ...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29172085/design-synthesis-and-pharmacological-evaluation-of-n-5-chloro-2-4-dihydroxybenzoyl-r-n-arylmethyl-1-2-3-4-tetrahydro-3-isoquinolinecarboxamides-as-potent-hsp90-inhibitors
#14
Chuanpeng Liang, Xingkang Wu, Zhenyu Li, Jing Zhu, Chunhua Lu, Yuemao Shen
Using diverse arylmethyl groups to replace the benzyl moiety of the lead Hsp90 inhibitor 1 (N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-benzyl-1,2,3,4-tetrahydro-3-iso quinolinecarboxamide), thirty four derivatives (10-43) were developed, and exhibited improved Hsp90 inhibitory and antiproliferative activities. SAR analysis indicated that the southeastern aryl substitutions influenced their antiproliferative activities obviously, with the para-pyridyl group (41) outperforming all other substitution patterns. In this regard, compound 41 was selected for further evaluation...
January 1, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29120638/discovery-and-optimization-of-potent-cell-active-pyrazole-based-inhibitors-of-lactate-dehydrogenase-ldh
#15
Ganesha Rai, Kyle R Brimacombe, Bryan T Mott, Daniel J Urban, Xin Hu, Shyh-Ming Yang, Tobie D Lee, Dorian M Cheff, Jennifer Kouznetsova, Gloria A Benavides, Katie Pohida, Eric J Kuenstner, Diane K Luci, Christine M Lukacs, Douglas R Davies, David M Dranow, Hu Zhu, Gary Sulikowski, William J Moore, Gordon M Stott, Andrew J Flint, Matthew D Hall, Victor M Darley-Usmar, Leonard M Neckers, Chi V Dang, Alex G Waterson, Anton Simeonov, Ajit Jadhav, David J Maloney
We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29048945/cell-density-affects-the-detection-of-chk1-target-engagement-by-the-selective-inhibitor-v158411
#16
Clara C Geneste, Andrew J Massey
Understanding drug target engagement and the relationship to downstream pharmacology is critical for drug discovery. Here we have evaluated target engagement of Chk1 by the small-molecule inhibitor V158411 using two different target engagement methods (autophosphorylation and cellular thermal shift assay [CETSA]). Target engagement measured by these methods was subsequently related to Chk1 inhibitor-dependent pharmacology. Inhibition of autophosphorylation was a robust method for measuring V158411 Chk1 target engagement...
February 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29026104/cetsa-quantitatively-verifies-in-vivo-target-engagement-of-novel-ripk1-inhibitors-in-various-biospecimens
#17
Tsuyoshi Ishii, Takuro Okai, Misa Iwatani-Yoshihara, Manabu Mochizuki, Satoko Unno, Masako Kuno, Masato Yoshikawa, Sachio Shibata, Masanori Nakakariya, Takatoshi Yogo, Tomohiro Kawamoto
The proof of target engagement (TE) is a key element for evaluating potential investment in drug development. The cellular thermal shift assay (CETSA) is expected to facilitate direct measurement of intracellular TE at all stages of drug development. However, there have been no reports of applying this technology to comprehensive animal and clinical studies. This report demonstrates that CETSA can not only quantitatively evaluate the drug-TE in mouse peripheral blood, but also confirm TE in animal tissues exemplified by using the receptor interacting protein 1 kinase (RIPK1) lead compound we have developed...
October 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28957646/a-high-throughput-dose-response-cellular-thermal-shift-assay-for-rapid-screening-of-drug-target-engagement-in-living-cells-exemplified-using-smyd3-and-ido1
#18
Dean E McNulty, William G Bonnette, Hongwei Qi, Liping Wang, Thau F Ho, Anna Waszkiewicz, Lorena A Kallal, Raman P Nagarajan, Melissa Stern, Amy M Quinn, Caretha L Creasy, Dai-Shi Su, Alan P Graves, Roland S Annan, Sharon M Sweitzer, Marc A Holbert
A persistent problem in early small-molecule drug discovery is the frequent lack of rank-order correlation between biochemical potencies derived from initial screens using purified proteins and the diminished potency and efficacy observed in subsequent disease-relevant cellular phenotypic assays. The introduction of the cellular thermal shift assay (CETSA) has bridged this gap by enabling assessment of drug target engagement directly in live cells based on ligand-induced changes in protein thermal stability...
January 2018: SLAS Discovery
https://www.readbyqxmd.com/read/28890935/ski-178-a-multitargeted-inhibitor-of-sphingosine-kinase-and-microtubule-dynamics-demonstrating-therapeutic-efficacy-in-acute-myeloid-leukemia-models
#19
Jeremy A Hengst, Taryn E Dick, Arati Sharma, Kenichiro Doi, Shailaja Hegde, Su-Fern Tan, Laura M Geffert, Todd E Fox, Arun K Sharma, Dhimant Desai, Shantu Amin, Mark Kester, Thomas P Loughran, Robert F Paulson, David F Claxton, Hong-Gang Wang, Jong K Yun
AIM: To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178. METHODS: Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML). RESULTS: Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2...
July 2017: Cancer Translational Medicine
https://www.readbyqxmd.com/read/28666623/geranylnaringenin-cg902-inhibits-constitutive-and-inducible-stat3-activation-through-the-activation-of-shp-2-tyrosine-phosphatase
#20
Yena Jin, Yae Jin Yoon, Yoon Jung Jeon, Jiyeon Choi, Yu-Jin Lee, Joonku Lee, Sangho Choi, Oyekanmi Nash, Dong Cho Han, Byoung-Mog Kwon
The roles and significance of signal transducer and activator of transcription 3 (STAT3) in human cancers have been extensively studied and STAT3 is a promising therapeutic target for cancer drug discovery. During the screening of natural products to identify STAT3 inhibitors, we identified geranylnaringenin (CG902), which decreased luciferase activity in a dose-dependent manner. CG902 specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cancer cells and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin...
October 15, 2017: Biochemical Pharmacology
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