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Dinaciclib

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https://www.readbyqxmd.com/read/29137354/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#1
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28947566/cytoplasmic-cyclin-e-mediates-resistance-to-aromatase-inhibitors-in-breast-cancer
#2
Iman Doostan, Cansu Karakas, Mehrnooh Kohansal, Kwang Hui Low, Matthew J Ellis, John A Olson, Vera Suman, Kelly Hunt, Stacy Moulder-Thompson, Khandan Keyomarsi
PURPOSE: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect...
September 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28942659/novel-synthetic-drugs-currently-in-clinical-development-for-chronic-lymphocytic-leukemia
#3
REVIEW
Pawel Robak, Tadeusz Robak
Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28938651/positive-transcription-elongation-factor-b-p-tefb-is-a-therapeutic-target-in-human-multiple-myeloma
#4
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/28859059/phase-1-safety-pharmacokinetic-and-pharmacodynamic-study-of-the-cyclin-dependent-kinase-inhibitor-dinaciclib-administered-every-three-weeks-in-patients-with-advanced-malignancies
#5
Monica M Mita, Alain C Mita, Jennifer L Moseley, Jennifer Poon, Karen A Small, Ying-Ming Jou, Paul Kirschmeier, Da Zhang, Yali Zhu, Paul Statkevich, Kamelesh K Sankhala, John Sarantopoulos, James M Cleary, Lucian R Chirieac, Scott J Rodig, Rajat Bannerji, Geoffrey I Shapiro
BACKGROUND: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity. METHODS: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined...
October 24, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28827110/synthesis-and-biological-evaluation-of-n9-cis-cyclobutylpurine-derivatives-for-use-as-cyclin-dependent-kinase-cdk-inhibitors
#6
Sun Jun Park, Eunjin Kim, Miyoun Yoo, Joo-Youn Lee, Chi Hoon Park, Jong Yeon Hwang, Jae Du Ha
A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28756008/efficacy-of-the-cdk-inhibitor-dinaciclib-in%C3%A2-vitro-and-in%C3%A2-vivo-in-t-cell-acute-lymphoblastic-leukemia
#7
Sausan A Moharram, Kinjal Shah, Fatima Khanum, Alissa Marhäll, Mohiuddin Gazi, Julhash U Kazi
T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL...
October 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28714472/targeting-the-differential-addiction-to-anti-apoptotic-bcl-2-family-for-cancer-therapy
#8
Akane Inoue-Yamauchi, Paul S Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C Pietanza, Matthew D Hellmann, Mark G Kris, James J Hsieh, Emily H Cheng
BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28545154/site-specific-phosphorylation-of-casein-kinase-1-%C3%AE-ck1%C3%AE-regulates-its-activity-towards-the-circadian-regulator-per2
#9
Gracie Wee Ling Eng, Edison, David M Virshup
Circadian rhythms are intrinsic ~24 hour cycles that regulate diverse aspects of physiology, and in turn are regulated by interactions with the external environment. Casein kinase 1 delta (CK1δ, CSNK1D) is a key regulator of the clock, phosphorylating both stabilizing and destabilizing sites on the PER2 protein, in a mechanism known as the phosphoswitch. CK1δ can itself be regulated by phosphorylation on its regulatory domain, but the specific sites involved, and the role this plays in control of circadian rhythms as well as other CK1-dependent processes is not well understood...
2017: PloS One
https://www.readbyqxmd.com/read/28361959/dinaciclib-potently-suppresses-mcl-1-and-selectively-induces-the-cell-death-in-human-ips-cells-without-affecting-the-viability-of-cardiac-tissue
#10
Khaled Alsayegh, Katsuhisa Matsuura, Hidekazu Sekine, Tatsuya Shimizu
Induced pluripotent stem (iPS) cells hold great potential for being a major source of cells for regenerative medicine. One major issue that hinders their advancement to clinic is the persistence of undifferentiated iPS cells in iPS-derived tissue. In this report, we show that the CDKs inhibitor, Dinaciclib, selectively eliminates iPS cells without affecting the viability of cardiac cells. We found that low nanomolar concentration of dinaciclib increased DNA damage and p53 protein levels in iPSCs. This was accompanied by negative regulation of the anti-apoptotic protein MCL-1...
March 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28295185/dual-targeting-of-mcl1-and-noxa-as-effective-strategy-for-treatment-of-mantle-cell-lymphoma
#11
Elisabeth Höring, Arnau Montraveta, Simon Heine, Markus Kleih, Lea Schaaf, Matthias C Vöhringer, Anna Esteve-Arenys, Gael Roué, Dolors Colomer, Elias Campo, German Ott, Walter E Aulitzky, Heiko van der Kuip
Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model...
May 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28249908/kinome-wide-rna-interference-screen-reveals-a-role-for-pdk1-in-acquired-resistance-to-cdk4-6-inhibition-in-er-positive-breast-cancer
#12
Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G Ericsson, Melinda E Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Teresa C Dugger, Wenyi Wei, Erik S Knudsen, Carlos L Arteaga
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines...
May 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28207834/a-cyclin-dependent-kinase-inhibitor-dinaciclib-in-preclinical-treatment-models-of-thyroid-cancer
#13
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Richard J Wong
BACKGROUND: We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer. MATERIALS AND METHODS: Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy...
2017: PloS One
https://www.readbyqxmd.com/read/28126927/efficacy-and-safety-of-dinaciclib-versus-ofatumumab-in-patients-with-relapsed-refractory-chronic-lymphocytic-leukemia
#14
Paolo Ghia, Lydia Scarfò, Susan Perez, Kumudu Pathiraja, Martha Derosier, Karen Small, Christine McCrary Sisk, Nigel Patton
No abstract text is available yet for this article.
January 26, 2017: Blood
https://www.readbyqxmd.com/read/28107181/cyclin-e-overexpression-as-a-biomarker-for-combination-treatment-strategies-in-inflammatory-breast-cancer
#15
Angela Alexander, Cansu Karakas, Xian Chen, Jason P W Carey, Min Yi, Melissa Bondy, Patricia Thompson, Kwok Leung Cheung, Ian O Ellis, Yun Gong, Savitri Krishnamurthy, Ricardo H Alvarez, Naoto T Ueno, Kelly K Hunt, Khandan Keyomarsi
Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/27991934/ras-oncogene-independent-activation-of-ralb-signaling-is-a-targetable-mechanism-of-escape-from-nras-v12-oncogene-addiction-in-acute-myeloid-leukemia
#16
E J Pomeroy, L A Lee, R D W Lee, D K Schirm, N A Temiz, J Ma, T A Gruber, E Diaz-Flores, B S Moriarity, J R Downing, K M Shannon, D A Largaespada, C E Eckfeldt
Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse...
June 8, 2017: Oncogene
https://www.readbyqxmd.com/read/27880910/cdk12-inhibition-reverses-de-novo-and-acquired-parp-inhibitor-resistance-in-brca-wild-type-and-mutated-models-of-triple-negative-breast-cancer
#17
Shawn F Johnson, Cristina Cruz, Ann Katrin Greifenberg, Sofia Dust, Daniel G Stover, David Chi, Benjamin Primack, Shiliang Cao, Andrea J Bernhardy, Rhiannon Coulson, Jean-Bernard Lazaro, Bose Kochupurakkal, Heather Sun, Christine Unitt, Lisa A Moreau, Kristopher A Sarosiek, Maurizio Scaltriti, Dejan Juric, José Baselga, Andrea L Richardson, Scott J Rodig, Alan D D'Andrea, Judith Balmaña, Neil Johnson, Matthias Geyer, Violeta Serra, Elgene Lim, Geoffrey I Shapiro
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27821810/investigating-the-mechanism-of-hepatocellular-carcinoma-progression-by-constructing-genetic-and-epigenetic-networks-using-ngs-data-identification-and-big-database-mining-method
#18
Cheng-Wei Li, Ping-Yao Chang, Bor-Sen Chen
The mechanisms leading to the development and progression of hepatocellular carcinoma (HCC) are complicated and regulated genetically and epigenetically. The recent advancement in high-throughput sequencing has facilitated investigations into the role of genetic and epigenetic regulations in hepatocarcinogenesis. Therefore, we used systems biology and big database mining to construct genetic and epigenetic networks (GENs) using the information about mRNA, miRNA, and methylation profiles of HCC patients. Our approach involves analyzing gene regulatory networks (GRNs), protein-protein networks (PPINs), and epigenetic networks at different stages of hepatocarcinogenesis...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765908/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#19
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27663592/selective-targeting-of-cyclin-e1-amplified-high-grade-serous-ovarian-cancer-by-cyclin-dependent-kinase-2-and-akt-inhibition
#20
George Au-Yeung, Franziska Lang, Walid J Azar, Chris Mitchell, Kate E Jarman, Kurt Lackovic, Diar Aziz, Carleen Cullinane, Richard B Pearson, Linda Mileshkin, Danny Rischin, Alison M Karst, Ronny Drapkin, Dariush Etemadmoghadam, David D L Bowtell
Purpose: Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1-amplified cancers and potential strategies to overcome resistance to targeted agents.Experimental Design: To examine dependency on CDK2 in CCNE1-amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor. High-throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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