浮米每周文献快讯：2015年01月（二）

浮米每周文献快讯：2015年01月（二） 作者：浮米网 来源：浮米网  2015-01-12

1. 原文标题及出处：
Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit
J. Med. Chem., 2015, 58 (1), pp 222–236
DOI: 10.1021/jm500669m
公司/组织：AbbVie Inc.
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靶点/作用机制：PKCθ抑制剂
摘要原文：
Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
备注：
抑制PKCθ能阻断T细胞激活，进而阻断T细胞反应。
Novartis和Vertex所研制的PKC抑制剂：

                               
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2. 原文标题及出处：

Discovery and Characterization of MAPK-activated Protein Kinase-2 Prevention of Activation Inhibitors

J. Med. Chem., 2015, 58 (1), pp 278–293

DOI: 10.1021/jm501038s

公司/组织：AstraZeneca

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靶点/作用机制：MAPK激活蛋白激酶2MK2a抑制剂

摘要原文：

Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure–activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α–MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.

备注：

许多p38α的小分子抑制剂能进入临床用于治疗慢性炎症，但是最终都没有成功上市，大部分由于副作用夭折于临床II期试验。MAPK激活蛋白激酶2MK2a（MAPKAP-kinase 2a或MK2a）可作为干扰p38α通路的另一个突破点。MK2的选择性抑制剂可有效于p38α抑制剂，但是可能会有更小的副作用。

3. 原文标题及出处：

Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis

J. Med. Chem., 2015, 58 (1), pp 333–346

DOI: 10.1021/jm5013006

公司/组织：AbbVie, Inc.

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靶点/作用机制：PKCθ抑制剂

摘要原文：

We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.

备注：

4. 原文标题及出处：

SAR156497, an Exquisitely Selective Inhibitor of Aurora Kinases

J. Med. Chem., 2015, 58 (1), pp 362–375

DOI: 10.1021/jm501326k

公司/组织：Sanofi

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靶点/作用机制：Aurora激酶抑制剂

摘要原文：

The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.

备注：

Aurora 激酶在有丝分裂中非常活跃，在细胞分裂中扮演着重要角色。

5. 原文标题及出处：

Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

J. Med. Chem., 2015, 58 (1), pp 376–400

DOI: 10.1021/jm5013352

公司/组织：Sanofi

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靶点/作用机制：Vps34抑制剂

摘要原文：

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

备注：

Vps34也称作PIK3C3。抑制Vps34可作为单治疗或联合治疗用于癌症患者。

6. 原文标题及出处：

Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models

J. Med. Chem., 2015, 58 (1), pp 401–418

DOI: 10.1021/jm5013984

公司/组织：Genentech

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靶点/作用机制：双亮氨酸拉链激酶（DLK， MAP3K12）抑制剂

摘要原文：

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.

备注：

双亮氨酸拉链激酶与JNK信号通路相关。

(by 浮米网)

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