Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

September 5th, 2016 by Gizem Ak├žay

Nature Chemical Biology 12, 931 (2016). doi:10.1038/nchembio.2174

Authors: Gizem Akçay, Matthew A Belmonte, Brian Aquila, Claudio Chuaqui, Alexander W Hird, Michelle L Lamb, Philip B Rawlins, Nancy Su, Sharon Tentarelli, Neil P Grimster & Qibin Su

  • Posted in Nat Chem Biol, Publications
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Small-molecule WNK inhibition regulates cardiovascular and renal function

September 5th, 2016 by Ken Yamada

Nature Chemical Biology 12, 896 (2016). doi:10.1038/nchembio.2168

Authors: Ken Yamada, Hyi-Man Park, Dean F Rigel, Keith DiPetrillo, Erin J Whalen, Anthony Anisowicz, Michael Beil, James Berstler, Cara Emily Brocklehurst, Debra A Burdick, Shari L Caplan, Michael P Capparelli, Guanjing Chen, Wei Chen, Bethany Dale, Lin Deng, Fumin Fu, Norio Hamamatsu, Kouki Harasaki, Tracey Herr, Peter Hoffmann, Qi-Ying Hu, Waan-Jeng Huang, Neeraja Idamakanti, Hidetomo Imase, Yuki Iwaki, Monish Jain, Jey Jeyaseelan, Mitsunori Kato, Virendar K Kaushik, Darcy Kohls, Vidya Kunjathoor, Daniel LaSala, Jongchan Lee, Jing Liu, Yang Luo, Fupeng Ma, Ruowei Mo, Sarah Mowbray, Muneto Mogi, Flavio Ossola, Pramod Pandey, Sejal J Patel, Swetha Raghavan, Bahaa Salem, Yuka H Shanado, Gary M Trakshel, Gordon Turner, Hiromichi Wakai, Chunhua Wang, Stephen Weldon, Jennifer B Wielicki, Xiaoling Xie, Lingfei Xu, Yukiko I Yagi, Kayo Yasoshima, Jianning Yin, David Yowe, Ji-Hu Zhang, Gang Zheng & Lauren Monovich

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

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Overcoming resistance to HER2 inhibitors through state-specific kinase binding

September 5th, 2016 by Chris J Novotny

Nature Chemical Biology 12, 923 (2016). doi:10.1038/nchembio.2171

Authors: Chris J Novotny, Sirkku Pollari, Jin H Park, Mark A Lemmon, Weijun Shen & Kevan M Shokat

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Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

August 29th, 2016 by Tanvi Shekhar-Guturja

Nature Chemical Biology 12, 867 (2016). doi:10.1038/nchembio.2165

Authors: Tanvi Shekhar-Guturja, G M Kamal B Gunaherath, E M Kithsiri Wijeratne, Jean-Philippe Lambert, Anna F Averette, Soo Chan Lee, Taeyup Kim, Yong-Sun Bahn, Farida Tripodi, Ron Ammar, Katja Döhl, Karolina Niewola-Staszkowska, Lutz Schmitt, Robbie J Loewith, Frederick P Roth, Dominique Sanglard, David Andes, Corey Nislow, Paola Coccetti, Anne-Claude Gingras, Joseph Heitman, A A Leslie Gunatilaka & Leah E Cowen

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Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

August 29th, 2016 by Tinghu Zhang

Nature Chemical Biology 12, 876 (2016). doi:10.1038/nchembio.2166

Authors: Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E Dixon-Clarke, Brian J Abraham, Ann K Greifenberg, Scott B Ficarro, Jonathan M Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L Greenleaf, Jarrod A Marto, Matthias Geyer, Alex N Bullock, Richard A Young & Nathanael S Gray

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Genetic code expansion in the mouse brain

August 29th, 2016 by Russell J Ernst

Nature Chemical Biology 12, 776 (2016). doi:10.1038/nchembio.2160

Authors: Russell J Ernst, Toke P Krogager, Elizabeth S Maywood, Roberto Zanchi, Václav Beránek, Thomas S Elliott, Nicholas P Barry, Michael H Hastings & Jason W Chin

Site-specific incorporation of non-natural amino acids into proteins, via genetic code expansion with pyrrolysyl tRNA synthetase (PylRS) and tRNAPylCUA pairs (and their evolved derivatives) from Methanosarcina sp., forms the basis of powerful approaches to probe and control protein function in cells and invertebrate organisms. Here we demonstrate that adeno-associated viral delivery of these pairs enables efficient genetic code expansion in primary neuronal culture, organotypic brain slices and the brains of live mice.

Fluorogenic probes reveal a role of GLUT4 N-glycosylation in intracellular trafficking

August 22nd, 2016 by Shinya Hirayama

Nature Chemical Biology 12, 853 (2016). doi:10.1038/nchembio.2156

Authors: Shinya Hirayama, Yuichiro Hori, Zsolt Benedek, Tadashi Suzuki & Kazuya Kikuchi

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Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin

August 22nd, 2016 by Zhong-Rui Li

Nature Chemical Biology 12, 773 (2016). doi:10.1038/nchembio.2157

Authors: Zhong-Rui Li, Jie Li, Jin-Ping Gu, Jennifer Y H Lai, Brendan M Duggan, Wei-Peng Zhang, Zhi-Long Li, Yong-Xin Li, Rong-Biao Tong, Ying Xu, Dong-Hai Lin, Bradley S Moore & Pei-Yuan Qian

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

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Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase

August 22nd, 2016 by Lavoisier Ramos-Espiritu

Nature Chemical Biology 12, 838 (2016). doi:10.1038/nchembio.2151

Authors: Lavoisier Ramos-Espiritu, Silke Kleinboelting, Felipe A Navarrete, Antonio Alvau, Pablo E Visconti, Federica Valsecchi, Anatoly Starkov, Giovanni Manfredi, Hannes Buck, Carolina Adura, Jonathan H Zippin, Joop van den Heuvel, J Fraser Glickman, Clemens Steegborn, Lonny R Levin & Jochen Buck

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Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices

August 22nd, 2016 by Gregory H Bird

Nature Chemical Biology 12, 845 (2016). doi:10.1038/nchembio.2153

Authors: Gregory H Bird, Emanuele Mazzola, Kwadwo Opoku-Nsiah, Margaret A Lammert, Marina Godes, Donna S Neuberg & Loren D Walensky

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