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https://www.readbyqxmd.com/read/29434052/in-vitro-and-in-vivo-anti-tumor-and-anti-inflammatory-capabilities-of-the-novel-gsk3-and-ckd9-inhibitor-abc1183
#1
Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines, Charles D Smith
Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate vital cellular functions such as proliferation, apoptosis and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy...
February 6, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29416031/cdk9-regulates-a-promoter-proximal-checkpoint-to-modulate-rna-polymerase-ii-elongation-rate-in-fission-yeast
#2
Gregory T Booth, Pabitra K Parua, Miriam Sansó, Robert P Fisher, John T Lis
Post-translational modifications of the transcription elongation complex provide mechanisms to fine-tune gene expression, yet their specific impacts on RNA polymerase II regulation remain difficult to ascertain. Here, in Schizosaccharomyces pombe, we examine the role of Cdk9, and related Mcs6/Cdk7 and Lsk1/Cdk12 kinases, on transcription at base-pair resolution with Precision Run-On sequencing (PRO-seq). Within a minute of Cdk9 inhibition, phosphorylation of Pol II-associated factor, Spt5 is undetectable. The effects of Cdk9 inhibition are more severe than inhibition of Cdk7 and Cdk12, resulting in a shift of Pol II toward the transcription start site (TSS)...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29415456/bet-family-protein-brd4-an-emerging-actor-in-nf%C3%AE%C2%BAb-signaling-in-inflammation-and-cancer
#3
REVIEW
Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin, Mary B Callanan
NFκB (Nuclear Factor- κ -light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb...
February 6, 2018: Biomedicines
https://www.readbyqxmd.com/read/29374194/2-phenylquinazolinones-as-dual-activity-tankyrase-kinase-inhibitors
#4
Yves Nkizinkiko, Jenny Desantis, Jarkko Koivunen, Teemu Haikarainen, Sudarshan Murthy, Luca Sancineto, Serena Massari, Federica Ianni, Ezeogo Obaji, Maria I Loza, Taina Pihlajaniemi, Jose Brea, Oriana Tabarrini, Lari Lehtiö
Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway...
January 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29335245/cdk9-mediated-phosphorylation-controls-the-interaction-of-tip60-with-the-transcriptional-machinery
#5
Prisca Brauns-Schubert, Florian Schubert, Manuela Wissler, Martina Weiss, Lisa Schlicher, Simon Bessler, Mariam Safavi, Cornelius Miething, Christoph Borner, Tilman Brummer, Ulrich Maurer
The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53-mediated induction of the BCL-2 protein PUMA. TIP60 phosphorylation by GSK-3 requires a priming phosphorylation on S90, and here, we identify CDK9 as a TIP60S90 kinase. We demonstrate that a phosphorylation-deficient mutant, TIP60S90A, exhibits reduced interaction with chromatin, histone 3 and RNA Pol II, while its association with the TIP60 complex subunit EPC1 is not affected...
January 15, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29329658/novel-compounds-with-potent-cdk9-inhibitory-activity-for-the-treatment-of-myeloma
#6
Zsófia Czudor, Mária Balogh, Péter Bánhegyi, Sándor Boros, Nóra Breza, Judit Dobos, Márk Fábián, Zoltán Horváth, Eszter Illyés, Péter Markó, Anna Sipos, Csaba Szántai-Kis, Bálint Szokol, László Őrfi
Cyclin-dependent kinases (CDKs) and Polo-like kinases (PLKs) play key role in the regulation of the cell cycle. The aim of our study was originally the further development of our recently discovered polo-like kinase 1 (PLK1) inhibitors. A series of new 2,4-disubstituted pyrimidine derivatives were synthesized around the original hit, but their PLK1 inhibitory activity was very poor. However the novel compounds showed nanomolar CDK9 inhibitory activity and very good antiproliferative effect on multiple myeloma cell lines (RPMI-8226)...
January 2, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29297149/repurposing-of-the-cdk-inhibitor-pha-767491-as-a-nrf2-inhibitor-drug-candidate-for-cancer-therapy-via-redox-modulation
#7
Hsiu-Yu Liu, Andrea Z Tuckett, Myles Fennell, Ralph Garippa, Johannes L Zakrzewski
Oxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress...
January 3, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29291023/combined-venetoclax-and-alvocidib-in-acute-myeloid-leukemia
#8
James Bogenberger, Clifford Whatcott, Nanna Hansen, Devora Delman, Chang-Xin Shi, Wontak Kim, Hillary Haws, Katherine Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman, Keith Stewart, David Bearss, Ruben Mesa, Steven Warner, Raoul Tibes
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29251720/pharmacological-perturbation-of-cdk9-using-selective-cdk9-inhibition-or-degradation
#9
Calla M Olson, Baishan Jiang, Michael A Erb, Yanke Liang, Zainab M Doctor, Zinan Zhang, Tinghu Zhang, Nicholas Kwiatkowski, Myriam Boukhali, Jennifer L Green, Wilhelm Haas, Tyzoon Nomanbhoy, Eric S Fischer, Richard A Young, James E Bradner, Georg E Winter, Nathanael S Gray
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets...
December 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#10
Liang Zhou, Yu Zhang, Deepak Sampath, Joel Leverson, Yun Dai, Maciej Kmieciak, Matthew Nguyen, Robert Z Orlowski, Steven Grant
BACKGROUND: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. METHODS: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo...
December 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29212213/the-bromodomain-and-extraterminal-domain-inhibitor-bromosporine-synergistically-reactivates-latent-hiv-1-in-latently-infected-cells
#11
Hanyu Pan, Panpan Lu, Yinzhong Shen, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, He Yang, Inam Ulla Khan, Muya Zhou, Bokang Li, Ziyu Zhang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
The long-lived latent HIV-1 reservoir is the major barrier for complete cure of Acquired Immune Deficiency Syndrome (AIDS). Here we report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate HIV-1 replication in different latency models alone and more powerful when combined with prostratin or TNF-α. Furthermore, the treatment with bromosporine induced HIV-1 full-length transcripts in resting CD4+ T cells from infected individuals with suppressive antiretroviral therapy (ART) ex vivo, with no obvious cytotoxicity or global activation of T cell...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29192216/bet-inhibitors-rvx-208-and-pfi-1-reactivate-hiv-1-from-latency
#12
Panpan Lu, Yinzhong Shen, He Yang, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, Hanyu Pan, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29177274/synthesis-of-4-substituted-pyrazole-3-5-diamines-via-suzuki-miyaura-coupling-and-iron-catalyzed-reduction
#13
Monika Tomanová, Lukáš Jedinák, Jan Košař, Lubomír Kvapil, Pavel Hradil, Petr Cankař
A general and efficient synthesis of 4-substituted-1H-pyrazole-3,5-diamines was developed to access derivatives with an aryl, heteroaryl, or styryl group, which are otherwise relatively difficult to prepare. The first step is based on the Suzuki-Miyaura cross-coupling reaction utilizing the XPhos Pd G2 precatalyst. The coupling reactions of 4-bromo-3,5-dinitro-1H-pyrazole with the electron-rich/deficient or sterically demanding boronic acids enabled the production of the corresponding dinitropyrazoles. The subsequent iron-catalyzed reduction of both nitro groups with hydrazine hydrate accomplished the synthesis...
November 27, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29170386/glucocorticoid-induced-phosphorylation-by-cdk9-modulates-the-coactivator-functions-of-transcriptional-cofactor-grip1-in-macrophages
#14
David A Rollins, Joubert B Kharlyngdoh, Maddalena Coppo, Bowranigan Tharmalingam, Sanda Mimouna, Ziyi Guo, Maria A Sacta, Miles A Pufall, Robert P Fisher, Xiaoyu Hu, Yurii Chinenov, Inez Rogatsky
The glucocorticoid (GC) receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein-1 (GRIP1) is a GR corepressor in macrophages, however, whether GRIP1 mediates GR-activated transcription, and what dictates its coactivator versus corepressor properties is unknown. Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator...
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29157894/selective-inhibition-reveals-cyclin-dependent-kinase-2-as-another-kinase-that-phosphorylates-the-androgen-receptor-at-serine-81
#15
Radek Jorda, Zuzana Bučková, Eva Řezníčková, Jan Bouchal, Vladimír Kryštof
Several studies have revealed that cyclin-dependent kinases (CDK) can mediate phosphorylation of steroid receptors at multiple sites, including serine 81 of the androgen receptor (AR). Phosphorylation of S81 is required for AR nuclear translocation in association with chromatin and also regulates endogenous AR-regulated transcription in response to hormones. Up to date, S81-phosphorylation has been studied using different CDK inhibitors. Nevertheless, most inhibitors are non-selective or have unknown selectivity...
November 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29156698/combined-brd4-and-cdk9-inhibition-as-a-new-therapeutic-approach-in-malignant-rhabdoid-tumors
#16
Natalia Moreno, Till Holsten, Julius Mertins, Annabelle Zhogbi, Pascal Johann, Marcel Kool, Michael Meisterernst, Kornelius Kerl
Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29144137/design-of-novel-3-pyrimidinylazaindole-based-cdk2-9-inhibitors-with-potent-in-vitro-and-in-vivo-antitumor-efficacy-in-a-triple-negative-breast-cancer-model
#17
Umed Singh, Gousia Chashoo, Sameer U Khan, Priya Mahajan, Amit Nargotra, Girish Mahajan, Amarinder Singh, Anjna Sharma, Mubashir Javeed Mintoo, Santosh Kumar Guru, Hariprasad Aruri, Thanusha Thatikonda, Promod Sahu, Pankaj Chibber, Vikas Kumar, Sameer A Mir, Sonali S Bharate, Sreedhar Madishetti, Utpal Nandi, Gurdarshan Singh, Dilip Manikrao Mondhe, Shashi Bhushan, Fayaz Malik, Serge Mignani, Ram A Vishwakarma, Parvinder Pal Singh
In the present study, novel series of 3-pyrimidinylazaindoles were designed and synthesized using bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in cell-cycle control and regulation of cell transcription. The present approach has given new dimensions to existing SAR and opens the new opportunity for lead optimization from comparatively inexpensive starting materials. The study led to the identification of alternative lead candidate 4ab with nanomolar potency against CDK2 and CDK9 and potent anti-proliferative activities against a panel of tested tumor cell lines along better safety ratio of ~30 in comparison to reported leads...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29133046/design-synthesis-and-biological-evaluation-of-novel-benzimidazole-amidines-as-potent-multi-target-inhibitors-for-the-treatment-of-non-small-cell-lung-cancer
#18
Andrea Bistrović, Luka Krstulović, Anja Harej, Petra Grbčić, Mirela Sedić, Sanja Koštrun, Sandra Kraljević Pavelić, Miroslav Bajić, Silvana Raić-Malić
A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29104242/synthesis-and-anti-proliferative-effects-of-mono-and-bis-purinomimetics-targeting-kinases
#19
Andrea Bistrović, Anja Harej, Petra Grbčić, Mirela Sedić, Sandra Kraljević Pavelić, Mario Cetina, Silvana Raić-Malić
A series of mono-pyrrolo[2,3-d]pyrimidines 4a-4k, unsymmetrical bis-purine isosteres 5a-5e and symmetrical bis-pyrrolo[2,3-d]pyrimidines 6a and 6b connected via di(1,2,3-triazolyl)phenyl linker were synthesized by click chemistry. Whereas mono- 4g and bis-pseudopurine 5e showed selective inhibitory activities on cervical carcinoma (HeLa) cells, bis-pyrrolo[2,3-d]pyrimidine 6b exhibited potent and selective anti-proliferative effect in the nanomolar range on pancreatic carcinoma (CFPAC-1) cells. Among these, compound 6b induced a significant reduction in the expression level of CDK9 (cyclin-dependent kinase 9)/cyclin T1 in CFPAC-1 cells concomitant with attenuation of proliferative signaling mediated by c-Raf (rapidly accelerated fibrosarcoma) and p38 MAP (mitogen-activated protein) kinases...
November 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29095844/ensemble-based-modeling-and-rigidity-decomposition-of-allosteric-interaction-networks-and-communication-pathways-in-cyclin-dependent-kinases-differentiating-kinase-clients-of-the-hsp90-cdc37-chaperone
#20
Gabrielle Stetz, Amanda Tse, Gennady M Verkhivker
The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences...
2017: PloS One
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