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https://www.readbyqxmd.com/read/29241222/flavopiridol-enhances-abt-199-sensitivity-in-unfavourable-risk-multiple-myeloma-cells-in-vitro-and-in-vivo
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/29077158/effects-of-caloric-restriction-on-peroxisome-proliferator-activated-receptors-and-positive-transcription-elongation-factor-b-expression-in-obese-rats
#12
Y-B Yang, X-L Wu, B Ke, Y-J Huang, S-Q Chen, Y-Q Su, J Qin
OBJECTIVE: To investigate the effect of caloric restriction (CR) on expressions of peroxisome proliferators-activated receptors (PPARs) and positive transcription elongation factor b (P-TEFb) (including cyclin-dependent kinase 9 (CDK9) and cyclin T1) protein in visceral adipose tissue of obese rats. MATERIALS AND METHODS: Obese rats were induced by high-fat diet for 8 weeks. Then they were divided into three groups: Model (n=5), 50% Calorie Restricted (50% CR, n=5), Intermittent Fasting (IF) (eight cycles of 3-d fasting and 3-d refeeding, n=6) for 8 weeks...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29063678/molecular-profiling-and-combinatorial-activity-of-cct068127-a-potent-cdk2-and-cdk9-inhibitor
#13
Steven R Whittaker, Clare Barlow, Mathew P Martin, Caterina Mancusi, Steve Wagner, Annette Self, Elaine Barrie, Robert Te Poele, Swee Sharp, Nathan Brown, Stuart Wilson, Wayne Jackson, Peter M Fischer, Paul A Clarke, Michael I Walton, Edward McDonald, Julian Blagg, Martin Noble, Michelle D Garrett, Paul Workman
Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28994650/cdk9-dependent-rna-polymerase-ii-pausing-controls-transcription-initiation
#14
Saskia Gressel, Björn Schwalb, Tim Michael Decker, Weihua Qin, Heinrich Leonhardt, Dirk Eick, Patrick Cramer
Gene transcription can be activated by decreasing the duration of RNA polymerase II pausing in the promoter-proximal region, but how this is achieved remains unclear. Here we use a 'multi-omics' approach to demonstrate that the duration of polymerase pausing generally limits the productive frequency of transcription initiation in human cells ('pause-initiation limit'). We further engineer a human cell line to allow for specific and rapid inhibition of the P-TEFb kinase CDK9, which is implicated in polymerase pause release...
October 10, 2017: ELife
https://www.readbyqxmd.com/read/28987604/discovery-and-synthesis-of-novel-wogonin-derivatives-with-potent-antitumor-activity-in%C3%A2-vitro
#15
Jubo Wang, Raoling Ge, Xiaqiu Qiu, Xi Xu, Libin Wei, Zhiyu Li, Jinlei Bian
Phenotypic screening of high quality compound library is one of the most effective strategy to obtain novel bioactive compounds. Recently, our group have constructed a Wogonin-scaffold library with substituents diversity and successfully obtained a series of potent compounds. Herein, we reported the synthesis of these compounds and evaluated the in vitro antitumor activity against a panel of human tumor cell lines. Most of them showed good activity with a broad spectrum and preliminary structure-activity relationship for the substitutions were obtained...
September 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28961375/identification-of-atuveciclib-bay%C3%A2-1143572-the-first-highly-selective-clinical-ptefb-cdk9-inhibitor-for-the-treatment-of-cancer
#16
Ulrich Lücking, Arne Scholz, Philip Lienau, Gerhard Siemeister, Dirk Kosemund, Rolf Bohlmann, Hans Briem, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Karsten Denner, Ulf Bömer, Martina Schäfer, Knut Eis, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Bert Klebl, Axel Choidas, Peter Nussbaumer, Matthias Baumann, Carsten Schultz-Fademrecht, Gerd Rühter, Jan Eickhoff, Michael Brands
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats...
September 29, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28954229/microprocessor-recruitment-to-elongating-rna-polymerase-ii-is-required-for-differential-expression-of-micrornas
#17
Victoria A Church, Sigal Pressman, Mamiko Isaji, Mary Truscott, Nihal Terzi Cizmecioglu, Stephen Buratowski, Maxim V Frolov, Richard W Carthew
The cellular abundance of mature microRNAs (miRNAs) is dictated by the efficiency of nuclear processing of primary miRNA transcripts (pri-miRNAs) into pre-miRNA intermediates. The Microprocessor complex of Drosha and DGCR8 carries this out, but it has been unclear what controls Microprocessor's differential processing of various pri-miRNAs. Here, we show that Drosophila DGCR8 (Pasha) directly associates with the C-terminal domain of the RNA polymerase II elongation complex when it is phosphorylated by the Cdk9 kinase (pTEFb)...
September 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/28940993/mir-206-inhibits-the-growth-of-hepatocellular-carcinoma-cells-via-targeting-cdk9
#18
Chi Pang, Gang Huang, Kaili Luo, Yuying Dong, Fengtian He, Guankui Du, Man Xiao, Wangwei Cai
miR-206 plays an important role in regulating the growth of multiple cancer cells. Cyclin-dependent kinase 9 (CDK9) stimulates the production of abundant prosurvival proteins, leading to impaired apoptosis of cancer cells. However, it is unknown whether CDK9 is involved in the miR-206-mediated growth suppression of hepatocellular carcinoma (HCC) cells. In this study, we found that the expression level of miR-206 was significantly lower in HCC cell lines than that in normal hepatic cell line (L02). Meanwhile, CDK9 was upregulated in HCC cell lines...
October 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28938651/positive-transcription-elongation-factor-b-p-tefb-is-a-therapeutic-target-in-human-multiple-myeloma
#19
Yu Zhang, Liang Zhou, Yun Leng, Yun Dai, Robert Z Orlowski, Steven Grant
The role of the positive RNA Pol II regulator, P-TEFb (positive transcription elongation factor b), in maintenance of the anti-apoptotic protein Mcl-1 and bortezomib (btz) resistance was investigated in human multiple myeloma (MM) cells. Mcl-1 was up-regulated in all MM lines tested, including bortezomib-resistant lines, human MM xenograft mouse models, and primary CD138(+) MM cells. Mcl-1 over-expression significantly reduced bortezomib lethality, indicating a functional role for Mcl-1 in bortezomib resistance...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935119/effects-of-cdk-inhibitors-on-the-maturation-transcription-and-mpf-activity-of-porcine-oocytes
#20
Reza K Oqani, Tao Lin, Jae Eun Lee, So Yeon Kim, Jung Won Kang, Dong Il Jin
In mammals, cyclin-dependent kinases (CDKs) are involved in regulating both the cell cycle and transcription. Although CDK1 is known to act as the kinase subunit of maturation-promoting factor (MPF), the roles of the other CDKs in mammalian oocyte maturation are not yet understood. Here, we show that inhibition of various CDKs by small molecule inhibitors has different effects on the maturation and transcriptional activity of pig oocytes in vitro. Inhibition of CDK1 did not significantly affect cumulus cell expansion, but its kinase activity was necessary for germinal vesicle breakdown (GVBD)...
September 18, 2017: Reproductive Biology
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