排序方式: 共有66条查询结果,搜索用时 140 毫秒
21.
Dr. Sang Min Lim Dr. Kenneth D. Westover Dr. Scott B. Ficarro Rane A. Harrison Dr. Hwan Geun Choi Dr. Michael E. Pacold Dr. Martin Carrasco Dr. John Hunter Dr. Nam Doo Kim Ting Xie Dr. Taebo Sim Dr. Pasi A. Jänne Dr. Matthew Meyerson Dr. Jarrod A. Marto Dr. John R. Engen Dr. Nathanael S. Gray 《Angewandte Chemie (International ed. in English)》2014,53(1):199-204
We report the synthesis of a GDP analogue, SML‐8‐73‐1, and a prodrug derivative, SML‐10‐70‐1, which are selective, direct‐acting covalent inhibitors of the K‐Ras G12C mutant relative to wild‐type Ras. Biochemical and biophysical measurements suggest that modification of K‐Ras with SML‐8‐73‐1 renders the protein in an inactive state. These first‐in‐class covalent K‐Ras inhibitors demonstrate that irreversible targeting of the K‐Ras guanine‐nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling. 相似文献
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Dr. Wenzhi Ji Dr. Woong Sub Byun Dr. Wenchao Lu Xijun Zhu Dr. Katherine A. Donovan Dr. Brendan G. Dwyer Dr. Jianwei Che Dr. Linjie Yuan Dr. Xianmixinuer Abulaiti Dr. Steven M. Corsello Dr. Eric S. Fischer Dr. Tinghu Zhang Dr. Nathanael S. Gray 《Angewandte Chemie (International ed. in English)》2023,62(43):e202308292
Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10 e , a first-in-class small molecule degrader of PDCD2. We discovered this PDCD2 degrader by serendipity using a chemical proteomics approach, in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10 e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights the use of chemical proteomics to discover selective small molecule degraders of unanticipated targets. 相似文献
23.
Dr. Mingxing Teng Dr. Jie Jiang Zhixiang He Dr. Nicholas P. Kwiatkowski Dr. Katherine A. Donovan Dr. Caitlin E. Mills Chiara Victor Dr. John M. Hatcher Dr. Eric S. Fischer Dr. Peter K. Sorger Dr. Tinghu Zhang Dr. Nathanael S. Gray 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(33):13969-13974
24.
Weill N Corbeil CR De Schutter JW Moitessier N 《Journal of computational chemistry》2011,32(13):2878-2889
The development and application of ACE, a program that predicts the stereochemical outcome of asymmetric reactions is presented. As major implementations, ACE includes a genetic algorithm to carry out an efficient global conformational search combined with a conjugate gradient minimization routine for local optimization and a corner flap algorithm to search ring conformations. Further improvements have been made that enable ACE to generate Boltzmann populations of conformations, to investigate highly asynchronous reactions, to compute fluctuating partial atomic charges and solvation energy and to automatically construct reactants and products from libraries of catalysts and substrates. Validation on previously investigated reactions (asymmetric Diels Alder cycloadditions and organocatalyzed aldol reactions) followed by application to a number of alkene epoxidation reactions and a comparative study of DFT-derived and ACE-derived predictions demonstrate the accuracy and usefulness of ACE in the context of asymmetric catalyst design. 相似文献
25.
Miduturu CV Deng X Kwiatkowski N Yang W Brault L Filippakopoulos P Chung E Yang Q Schwaller J Knapp S King RW Lee JD Herrgard S Zarrinkar P Gray NS 《Chemistry & biology》2011,18(7):868-879
Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors. 相似文献
26.
Nathanaël Guigo Nicolas Sbirrazzuoli Sergey Vyazovkin 《Macromolecular rapid communications》2012,33(8):698-702
Diluted (1.0–1.5 wt%) aqueous gelatin solutions have been cooled to –10 °C at a cooling rate 20 °C min−1 without freezing and detectable gelation. When heated at a constant heating rate (0.5 –2 °C min−1), the obtained supercooled solutions demonstrate an atypical process of gelation that has been characterized by regular and stochastically modulated differential scanning calorimetry (DSC) as well as by isoconversional kinetic analysis. The process is detectable as an exothermic peak in the total heat flow of regular DSC and in the nonreversing heat flow of stochastically modulated DSC. Isoconversional kinetic analysis applied to DSC data reveals that the effective activation energy of the process increases from approximately 75 to 200 kJ mol−1 as a supercooled solution transforms to gel on continuous h eating. 相似文献
27.
Baishan Jiang Eric S. Wang Katherine A. Donovan Yanke Liang Eric S. Fischer Tinghu Zhang Nathanael S. Gray 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(19):6387-6392
Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well‐established targets of imide‐based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions. 相似文献
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29.
Wan Y Hur W Cho CY Liu Y Adrian FJ Lozach O Bach S Mayer T Fabbro D Meijer L Gray NS 《Chemistry & biology》2004,11(2):247-259
Hymenialdisine (HMD) is a sponge-derived natural product kinase inhibitor with nanomolar activity against CDKs, Mek1, GSK3beta, and CK1 and micromolar activity against Chk1. In order to explore the broader application of the pyrrolo[2,3-c]azepine skeleton of HMD as a general kinase inhibitory scaffold, we searched for additional protein targets using affinity chromatography in conjunction with the synthesis of diverse HMD analogs and profiled HMD against a panel of 60 recombinant enzymes. This effort has led to nanomolar to micromolar inhibitors of 11 new targets including p90RSK, KDR, c-Kit, Fes, MAPK1, PAK2, PDK1, PKCtheta, PKD2, Rsk1, and SGK. The synthesis of HMD analogs has resulted in the identification of compounds with enhanced and/or dramatically altered selectivities relative to HMD (28n) and in molecules with antiproliferative activities 30-fold higher than HMD (28p). 相似文献
30.
Priest C Stevens N Sedev R Skinner W Ralston J 《Journal of colloid and interface science》2008,320(2):563-568
Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been examined as a possible predictive tool for surface wettability. Heterogeneous surfaces were prepared with hydrophilic and hydrophobic regions of known surface coverage using self-assembled monolayers. The surface coverage of each component was then correlated with ToF-SIMS fragmentation of the hydrophobic and hydrophilic surface groups and static contact angle measurements. From these measurements, a clear relationship between the surface wettability and relative intensity of characteristic secondary ions was identified. Moreover, our results for planar surfaces can be extrapolated to predict the wettability of particulate samples for which direct contact angle measurements are not straightforward. The ability to infer particle wettability by ToF-SIMS is well suited to mineral characterization and in particular, the prediction of mineral flotation efficiencies. 相似文献