Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs

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• 作者：Shun Ying Quah^a ; ¹ ; Michelle Siying Tan^a ; ¹ ; Yuan Han Teh^a ; ¹ ; Johnson Stanslas^a ; ^b ; ^{rcxjs@upm.edu.my" class="auth_mail" title="E-mail the corresponding author} ; ^{jstanslas@yahoo.co.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AGP ; Andrographolide ; APT1 ; Acyl protein thioesterase 1 ; COX-2 ; cyclooxygenase-2 ; DPI ; Dual prenylation inhibitor ; ERK ; Extracellular signal-regulated kinase ; FBDD ; Fragment-based drug discovery ; FTase ; Farnesyltransferase ; FTIs ; Farnesyltransferase inhibitors ; G12 ; Glycine-12 ; G13 ; Glycine-13 ; Q61 ; Glutamine-61 ; GAP ; GTPase-activating protein ; GDP ; Guanosine diphosphate ; GEF ; Guanine nucleotide exchange factor ; GGTase I ; Geranylgeranyltransferase I ; GGTI ; Geranylgeranyltransferase inhibitor ; GT
• 刊名：Pharmacology and Therapeutics
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：162
• 期：Complete
• 页码：35-57
• 全文大小：2776 K

文摘

Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered “undruggable” until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras–effector interaction, interference of Ras membrane association, prevention of Ras–guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras–guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin.