浮米每周文献快讯：2015年04月（四）

前沿        作者：浮米网 来源：浮米网  2015-04-26 0评论

1. 原文标题及出处：

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

J. Med. Chem., 2015, 58 (8), pp 3611–3625

DOI: 10.1021/acs.jmedchem.5b00352

公司/组织：AstraZeneca

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：PFKFB3激酶抑制剂

摘要原文：

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

备注：

糖酵解过程中一个关键步骤是果糖-6-磷酸（F6P）在磷酸果糖激酶-1（PFK-1）的催化下转化为果糖-1,6-双磷酸（F-1,6-BP），PFK-1的活性受到ATP、ADP、AMP、果糖-2,6-双磷酸（F-2,6-BP）的调控，其中果糖-2,6-双磷酸是PFK-1最强的激活剂。PFKFB (phosphofructokinase-2/fructose-2,6-bisphosphatase)是一类双功能酶，催化果糖-2,6-双磷酸的合成和水解。PFKFB3在一系列癌症中高表达，包括乳腺癌、前列腺癌、直肠癌、星形细胞癌、卵巢癌等，而它的表达或活性也与预后差有关。

2. 原文标题及出处：

Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors

J. Med. Chem., 2015, 58 (8), pp 3548–3571

DOI: 10.1021/jm502009h

公司/组织：GlaxoSmithKline

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：CD38抑制剂

摘要原文：

A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.

备注：

NAD是许多酶的底物，包括CD38。CD38是一个II型的定位于膜上的催化酶。它能催化NAD的降解。

3. 原文标题及出处：

Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

J. Med. Chem., 2015, 58 (8), pp 3522–3533

DOI: 10.1021/acs.jmedchem.5b00066

公司/组织：AstraZeneca

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：雌激素受体下调剂

摘要原文：

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

备注：

一些雌激素受体的配体、调节剂、下调剂：

                               
登录/注册后可看大图

受教了…………