STK19の薬理学的ターゲティングは,腫瘍性NRAS駆動メラノゲネシスを阻害する
Chengqian Yin1, Bo Zhu1, Ting Zhang2
1Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Cell
|February 5, 2019
まとめ
研究者らは,STK19をメラノーマにおける新しいNRAS活性化剤として発見した. STK19をZT-12-037-01で標的にすることは,NRAS変異のメラノーマに対する有望な治療戦略です.
科学分野:
- 腫瘍学
- 分子生物学
- 生物化学
背景:
- NRAS変異の活性化が メラノーマの20~30%を誘発しますが 効果的な治療法は未だに未定です
- BRAFとは異なり,NRASの腫瘍誘発因子には標的型の治療戦略がない.
- NRASの活性化メカニズムを理解することは,新しいメラノーマ治療法の開発に不可欠です.
研究 の 目的:
- メラノーマにおけるNRASの新規活性化剤を特定する.
- NRAS媒介メラノーマゲネシスにおけるSTK19の役割を調査する.
- NRAS変異のメラノーマに対するSTK19標的阻害剤の開発と評価.
主な方法:
- STK19をNRASアクティベーターとして生化学的測定で特定する.
- NRASのSTK19リン酸化とその下流効果の特徴
- STK19 D89NノッキンモデルとSTK19阻害剤ZT-12-037-01を用いたインビボ試験
主要な成果:
- STK19は,NRASを活性化する新しいセリン/スレオニンキナーゼとして特定されました.
- STK19は下流エフェクターへのNRAS結合を強化し,悪性変異を促進します.
- メラノーマの25%で発見された機能増強STK19 D89N変異はNRASの活性を増強する.
- ZT-12-037-01によるSTK19抑制は,メラノーマの成長をin vitroおよびin vivoで効果的に阻害する.
結論:
- STK19はメラノーマにおける腫瘍性NRASの重要な活性化剤である.
- STK19 D89Nはメラノーマのサブセットにおける重要な腫瘍発生因子である.
- STK19をZT-12-037-01のような阻害剤で標的化することは,NRAS変異のメラノーマに対する有効な治療戦略です.
関連する概念動画
00:46Feedback Inhibition
57.1K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.1K
01:33Cancer-Critical Genes I: Proto-oncogenes
11.5K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
11.5K
01:30Enzyme Inhibition
92.2K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
92.2K
01:27ATP Driven Pumps I: An Overview
9.8K
ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...
9.8K
02:34Inhibition of Cdk Activity
6.0K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.0K
01:28Cholinergic Antagonists: Pharmacological Actions
1.7K
Antimuscarinic drugs block muscarinic receptors in multiple systems, including the gut, eye, smooth muscles, respiratory tract, cardiovascular, and central nervous systems. They produce similar effects with varying selectivity depending on the specific agent and tissue. Here are the key pharmacological actions of antimuscarinics:
Gastrointestinal Effects: Antimuscarinics reduce gut contractions, increase gastric emptying, and slow intestinal transit. They partly inhibit gastric acid secretion...
Gastrointestinal Effects: Antimuscarinics reduce gut contractions, increase gastric emptying, and slow intestinal transit. They partly inhibit gastric acid secretion...
1.7K