文献精读系列一：Part A 文献征集

dejunchem

文献精读系列一：Part A 文献精选

      为发挥团体优势，增进论坛内部交流，经与大家商议拟举办文献精读系列。本次活动仅为一次尝试，还有很多不足，会积极听取大家意见！
      好的文献是一个良好的开始，由于时间紧张，我粗选了3片文献，大家投票看看精读哪一篇。由于本人水平有限，文献所选不合适之处，还请大家谅解。另外群友也可以提供好的经典文献，提供相关文献者奖励10金币。
       以下是文章摘要部分，时间关系不能为大家提供翻译了。
      希望大家能够支持！

dejunchem

1
Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

Nature Communications 3 ISSN (online): 2041-1723
http://www.nature.com/ncomms/journal/v3/n12/full/ncomms2304.html

dejunchem

2
De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation

The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads. A binding model was developed and a set of guidelines were then selected to use this model to design fragments, enabling our discovery of a novel fragment with high LE.

J. Med. Chem., 2013, 56 (7), pp 3115–3119

http://pubs.acs.org/doi/abs/10.1021/jm4002605

dejunchem

3

Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors

                                              基于电片段的可逆性共价激酶抑制剂的合理设计

ABSTRACT: Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient  ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.
          摘要：基于片段化的配体设计和靶向非催化域色氨酸的手段以成为开发具有高效性，高选择性激酶抑制剂的重要手段。在这片报到里，我们联合这些策略，以我们先去证实具有较好可逆性共价修饰色氨酸硫醇键的小分子, 芳香基团取代氰基丙烯酰胺为起始分子，运用这些策略，我们首次报到了在电性和选择性均能很好锲和激酶MSK1碳末端的选择性高效性配体。再借助单晶衍射，引入吲哚优势片段，得到了骨架12（化合物RMM-46）。这个分子在可逆性和选择性抑制MSK/RSK家族激酶上表现出极为优越的活性：在纳摩尔级别即能好阻断细胞内MSK和RSK的激活，并且现在的下调关键转录因子 CREB的磷酸化水平。

J. Am. Chem. Soc., 2013, 135 (14), pp 5298–5301

http://www.bioms.org/thread-499-1-1.html
http://pubs.acs.org/doi/abs/10.1021/ja401221b

西大-song

dejunchem 发表于 2013-4-15 20:13

                               
登录/注册后可看大图

1
Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

望哥，我的是硫基转移酶