Novel Strategies to Tackle Ras-Related Cancer: An Opinion Based on Two Recent Reviews

In this communication, we provide a brief overview of two recent reviews by [1,2] which highlight the importance of the continued need for the development of small molecule inhibitors to modulate abnormal signaling processes stimulated by the Ras GTPases. If not properly regulated, these signaling processes can result in Ras-stimulated hyperactivity that can lead to diseases such as cancer. However, to date, strategies to target inhibition of these proteins still remains a daunting challenge. Therefore, these proteins remain important targets for drug discovery efforts to control Ras-stimulated abnormal cell signaling.


Opinion
In this communication, we provide a brief overview of two recent reviews by [1,2] which highlight the importance of the continued need for the development of small molecule inhibitors to modulate abnormal signaling processes stimulated by the Ras GTPases. If not properly regulated, these signaling processes can result in Ras-stimulated hyperactivity that can lead to diseases such as cancer. However, to date, strategies to target inhibition of these proteins still remains a daunting challenge. Therefore, these proteins remain important targets for drug discovery efforts to control Ras-stimulated abnormal cell signaling.
Evidence continues to show that members of the Ras-related GTPases undergo deregulated mechanisms that can lead to cancer.
These proteins are involved in several cell signaling activities that are vital to processes such as cell proliferation and differentiation that, if not properly regulated, can result in an oncogenic state [1].
This issue underlies their importance as targets for drug discovery efforts to control Ras-stimulated abnormal cell signaling. Recent reviews by [2], as well as Prieto Dominguez, Parnell & Teng [1] have highlighted the importance of small molecule drug targeting to modulate abnormal Ras-stimulated signaling processes. This protein family serves as binary molecular switches that cycle between active-(GTP-linked) and inactive-(GDP-linked) bound states that help to regulate numerous cellular processes. These small GTPases exhibit intrinsic albeit slow GTP hydrolysis activity and therefore exist predominantly in vivo in the GDP linked inactive state until activated by guanine-nucleotide exchange factors (GEFs), which replaces the bound GDP with GTP. In addition, the enzymes interact with GTPase-activating proteins (GAPs) which cause deactivation by stimulating the hydrolysis of GTP to GDP ( [1] and references therein).
The noted reviews discuss recent approaches/mechanisms towards the inhibition of Ras-related proteins in various cancers caused by overexpression, mutation(s), hyperactivity, or undesired Protein-Protein Interactions (PPIs). Designing and identifying particular small molecule inhibitors to decrease and/or eliminate abnormal cell signaling would represent a major step forward in cancer therapies ( Figure 1). Target inhibitors of the Ras-related protein ADP ribosylation factor 1 (Arf1) include LM11, Exo2, Brefeldin A (BFA), AMF-26 which function to alter the making of the Arf1-GEF assembly by hampering the GEF activity as described by [1] and references therein). The small molecule Sec7 inhibitor H3 (SecinH3), a non-specific inhibitor of Arf, was described as being able to block signaling activities of Arf1 and Arf6 through binding to the ARF Nucleotide-Binding site Opener (ARNO) Sec7 catalytic domain and thereby deactivating small ARF-specific GEFs [3]. potential hyperactivity. The two reviews also highlighted some new possibilities to inhibit Ras oncogenic activities, through the use of library screenings, including Bisphenol A and its derivatives 4,4'-biphenol, SCH-53870 and SAH-SOS1 [6] as well as SCH-54292 [7] which targeted NIH3T3 cell proliferation in an apoptotic-dependent manner. [2] also cited metal-cyclens, organometallic molecules containing bivalent metals such as Zn2+, Co2+ or Cu2+, which were shown to exert potential inhibitory impact on Ras oncogenic activities [8]. and references therein). Moreover, targeting Ras-related proteins to inhibit their attachment to the cell membrane, thereby reducing their activity has also been shown to be a promising approach.
The small molecules Salirasib (transfarnesylthiosalicylic acid) and Secramine A were highlighted as having inhibitory effects on small GTPase attachment thereby influencing their hyperactive potential ([1,2] and references therein). It is also worth mentioning that, in addition to highlighting demonstrations of promising results both in vivo an in vitro in the design and development of more potent chemical Ras proteins inhibitors, the reviews also pointed out the potential of non-chemical strategies.
The design of killer genes with the potential of knocking down Ras genes essential for tumerigenesis, as noted by [5], was suggested as an alternative approach to suppress Ras protein activity given issues related to developing potent and effective "Direct" Ras inhibitors. The inhibition of sub-family members of Ras is also an important approach to combat hyperactivity leading to the oncogenic state. Both reviews by [1,2], and references therein, Currently, there are no small GTPase inhibitors used in clinical treatments to address the abnormal activity of these proteins.
Although these proteins contribute to several types of cancers, issues related to finding surface areas to serve as binding sites for these small molecule inhibitors still remain a hurdle. Indeed, there is still much work needed in the development of suitable inhibitors to treat small GTPase-stimulated cancers with great efficacy. Nevertheless, the reviews of [1,2] have showcased several promising developments in this regard.