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james bradner

Sara Bolin, Anna Borgenvik, Camilla U Persson, Anders Sundström, Jun Qi, James E Bradner, William A Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J Swartling
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively...
March 7, 2018: Oncogene
Lara N Gechijian, Dennis L Buckley, Matthew A Lawlor, Jaime M Reyes, Joshiawa Paulk, Christopher J Ott, Georg E Winter, Michael A Erb, Thomas G Scott, Mousheng Xu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Nicholas P Kwiatkowski, Jennifer A Perry, Jun Qi, Nathanael S Gray, James E Bradner
The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24...
March 5, 2018: Nature Chemical Biology
Jonathan D Brown, Zachary B Feldman, Sean P Doherty, Jaime M Reyes, Peter B Rahl, Charles Y Lin, Quanhu Sheng, Qiong Duan, Alexander J Federation, Andrew L Kung, Saptarsi M Haldar, Richard A Young, Jorge Plutzky, James E Bradner
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation...
February 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Rhamy Zeid, Matthew A Lawlor, Evon Poon, Jaime M Reyes, Mariateresa Fulciniti, Michael A Lopez, Thomas G Scott, Behnam Nabet, Michael A Erb, Georg E Winter, Zoe Jacobson, Donald R Polaski, Kristen L Karlin, Rachel A Hirsch, Nikhil P Munshi, Thomas F Westbrook, Louis Chesler, Charles Y Lin, James E Bradner
Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy...
January 29, 2018: Nature Genetics
Mette Ishoey, Someth Chorn, Natesh Singh, Martin G Jaeger, Matthias Brand, Joshiawa Paulk, Sophie Bauer, Michael A Erb, Katja Parapatics, André C Müller, Keiryn L Bennett, Gerhard F Ecker, James E Bradner, Georg E Winter
Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752...
January 22, 2018: ACS Chemical Biology
Jay H Kalin, Muzhou Wu, Andrea V Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J Roberts, Justin M Roberts, Polina Prusevich, Jeliazko R Jeliazkov, Shourya S Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M Proby, Albena T Dinkova-Kostova, Wayne W Hancock, Jeffrey J Gray, James E Bradner, Sergio Valente, Antonello Mai, Nicole M Anders, Michelle A Rudek, Yong Hu, Byungwoo Ryu, John W R Schwabe, Andrea Mattevi, Rhoda M Alani, Philip A Cole
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes...
January 4, 2018: Nature Communications
Stephen C Mack, Kristian W Pajtler, Lukas Chavez, Konstantin Okonechnikov, Kelsey C Bertrand, Xiuxing Wang, Serap Erkek, Alexander Federation, Anne Song, Christine Lee, Xin Wang, Laura McDonald, James J Morrow, Alina Saiakhova, Patrick Sin-Chan, Qiulian Wu, Kulandaimanuvel Antony Michaelraj, Tyler E Miller, Christopher G Hubert, Marina Ryzhova, Livia Garzia, Laura Donovan, Stephen Dombrowski, Daniel C Factor, Betty Luu, Claudia L L Valentim, Ryan C Gimple, Andrew Morton, Leo Kim, Briana C Prager, John J Y Lee, Xiaochong Wu, Jennifer Zuccaro, Yuan Thompson, Borja L Holgado, Jüri Reimand, Susan Q Ke, Adam Tropper, Sisi Lai, Senthuran Vijayarajah, Sylvia Doan, Vaidehi Mahadev, Ana Fernandez Miñan, Susanne N Gröbner, Matthias Lienhard, Marc Zapatka, Zhiqin Huang, Kenneth D Aldape, Angel M Carcaboso, Peter J Houghton, Stephen T Keir, Till Milde, Hendrik Witt, Yan Li, Chao-Jun Li, Xiu-Wu Bian, David T W Jones, Ian Scott, Sheila K Singh, Annie Huang, Peter B Dirks, Eric Bouffet, James E Bradner, Vijay Ramaswamy, Nada Jabado, James T Rutka, Paul A Northcott, Mathieu Lupien, Peter Lichter, Andrey Korshunov, Peter C Scacheri, Stefan M Pfister, Marcel Kool, Michael D Taylor, Jeremy N Rich
Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy...
December 20, 2017: Nature
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
Maria Kleppe, Richard Koche, Lihua Zou, Peter van Galen, Corinne E Hill, Lauren Dong, Sofie De Groote, Efthymia Papalexi, Amritha V Hanasoge Somasundara, Keith Cordner, Matthew Keller, Noushin Farnoud, Juan Medina, Erin McGovern, Jaime Reyes, Justin Roberts, Matthew Witkins, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E Bernstein, James E Bradner, Ross L Levine
Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN...
December 1, 2017: Cancer Cell
Rui Su, Lei Dong, Chenying Li, Sigrid Nachtergaele, Mark Wunderlich, Ying Qing, Xiaolan Deng, Yungui Wang, Xiaocheng Weng, Chao Hu, Mengxia Yu, Jennifer Skibbe, Qing Dai, Dongling Zou, Tong Wu, Kangkang Yu, Hengyou Weng, Huilin Huang, Kyle Ferchen, Xi Qin, Bin Zhang, Jun Qi, Atsuo T Sasaki, David R Plas, James E Bradner, Minjie Wei, Guido Marcucci, Xi Jiang, James C Mulloy, Jie Jin, Chuan He, Jianjun Chen
R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways...
December 11, 2017: Cell
Abraham S Weintraub, Charles H Li, Alicia V Zamudio, Alla A Sigova, Nancy M Hannett, Daniel S Day, Brian J Abraham, Malkiel A Cohen, Behnam Nabet, Dennis L Buckley, Yang Eric Guo, Denes Hnisz, Rudolf Jaenisch, James E Bradner, Nathanael S Gray, Richard A Young
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF...
December 14, 2017: Cell
Liying Chen, Gabriela Alexe, Neekesh V Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A Weir, Glenn S Cowley, Levi D Ali, Sasha Pantel, Guozhi Jiang, William F Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M Krill-Burger, Robin M Meyers, Aviad Tsherniak, David E Root, James E Bradner, Todd R Golub, Charles Wm Roberts, William C Hahn, William A Weiss, Carol J Thiele, Kimberly Stegmaier
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo...
January 2, 2018: Journal of Clinical Investigation
Graham S Erwin, Matthew P Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N Syed, Asuka Eguchi, Md Ashraf, Justin Jeffery, Mousheng Xu, Paul M C Park, Hasan Mukhtar, Achal K Srivastava, Mohammed Faruq, James E Bradner, Aseem Z Ansari
The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators...
December 22, 2017: Science
Rebecca Kohnken, Jing Wen, Bethany Mundy-Bosse, Kathleen McConnell, Ashleigh Keiter, Leah Grinshpun, Alex Hartlage, Max Yano, Betina McNeil, Nitin Chakravarti, Basem William, James E Bradner, Michael A Caligiuri, Pierluigi Porcu, Anjali Mishra
MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4+ T cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells...
February 15, 2018: Blood
Giovanni Roti, Jun Qi, Samuel Kitara, Marta Sanchez-Martin, Amy Saur Conway, Anthony C Varca, Angela Su, Lei Wu, Andrew L Kung, Adolfo A Ferrando, James E Bradner, Kimberly Stegmaier
On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage...
November 20, 2017: Journal of Experimental Medicine
Patrick L Garcia, Aubrey L Miller, Tracy L Gamblin, Leona N Council, John D Christein, J Pablo Arnoletti, Marty J Heslin, Sushanth Reddy, Joseph H Richardson, Xiangqin Cui, Robert C A M van Waardenburg, James E Bradner, Eddy S Yang, Karina J Yoon
Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA...
November 15, 2017: Molecular Cancer Therapeutics
Hai-Tsang Huang, Dennis Dobrovolsky, Joshiawa Paulk, Guang Yang, Ellen L Weisberg, Zainab M Doctor, Dennis L Buckley, Joong-Heui Cho, Eunhwa Ko, Jaebong Jang, Kun Shi, Hwan Geun Choi, James D Griffin, Ying Li, Steven P Treon, Eric S Fischer, James E Bradner, Li Tan, Nathanael S Gray
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable...
November 7, 2017: Cell Chemical Biology
Teru Hideshima, Ralph Mazitschek, Jun Qi, Naoya Mimura, Jen-Chieh Tseng, Andrew L Kung, James E Bradner, Kenneth C Anderson
We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition...
October 6, 2017: Oncotarget
Jingwei Cheng, Donglim Esther Park, Christian Berrios, Elizabeth A White, Reety Arora, Rosa Yoon, Timothy Branigan, Tengfei Xiao, Thomas Westerling, Alexander Federation, Rhamy Zeid, Benjamin Strober, Selene K Swanson, Laurence Florens, James E Bradner, Myles Brown, Peter M Howley, Megha Padi, Michael P Washburn, James A DeCaprio
Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry...
October 2017: PLoS Pathogens
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
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