Mini Reviews in Medicinal Chemistry - Volume 16, Issue 5, 2016

For decades, mutant Ras (mut-Ras) proteins have been identified as drivers of multiple cancers including pancreatic, lung, and colon cancers. However, targeting this oncogene has been challenging and no Ras inhibitors are on the market to date. Lately several candidates targeting the downstream pathways of Ras signaling, including PI3K and Raf, were approved for cancer treatment. However, they do not present promising therapeutic effects on patients harboring Ras mutations. Recently, a variety of compounds have been reported to impair the activity of Ras, and these exciting discoveries reignite the hope for development of novel drugs targeting mut-Ras. In this article, we will review the progress made in this field and the current state-of-the-art technologies to develop Ras inhibitors. Also we will discuss the future direction of targeting Ras.

Oncogenic Ras proteins are a driving force in a significant set of human cancers and wildtype, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre-clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development.

RAS is a molecular switch that regulates a large number of pathways through interactions with many effector proteins. Most RAS/effector complexes are short-lived, demonstrating fast association and fast dissociation rate and Kds ranging from 10-8–10-5 M, compatible with the signaling function of these interactions in the cell. RAS effectors share little sequence homology but all contain an RAS binding domain that exhibits ubiquitin fold. All effectors bind to the same epitope on RAS by forming an intermolecular beta sheet and creating a number of favorable hydrogen bonds and salt bridges across the binding interface. Several hot-spots on both RAS and effector molecules constitute a general recognition mode. RAS/effector interactions occur only when RAS is found in the active, GTP-bound state, and are disrupted upon GTP hydrolysis, most probably due to increased flexibility of the RAS molecule. Recent NMR studies demonstrate how in the presence of multiple binding partners, RAS prefers certain effectors to others. The hierarchy of these interactions could be altered for RAS oncogenic mutants, thus perturbing the network of the downstream signaling. Insights obtained through biophysical and structural studies of effectors interacting with RAS and its mutants establish the basic principles that could be used for designing drugs in RAS-associated diseases.

Activating Ras mutations are associated with ~30% of all human cancers, which often respond poorly to standard therapies. The four Ras isoforms are therefore highly attractive targets for anticancer drug discovery. However, Ras proteins function through protein-protein interactions and their surfaces lack any major pockets for small molecules to bind; as a result they have been declared “undruggable” for the past 30 years. Several breakthroughs during the past few years may finally remove Ras from the list of undruggable proteins. This mini-review discusses the current approaches to developing inhibitors especially cyclic peptides that physically block the interaction between Ras and its downstream effector proteins, which is potentially the most effective approach for treating Ras mutant cancers.

Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS mutant. In this mini-review, we first assess the development and targeting strategies associated with novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors.

The K-, N-, and HRas small GTPases are key regulators of cell physiology and are frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive Ras based on known mechanisms of Ras signaling have been met with little success. Several studies have provided compelling evidence for the existence and biological relevance of Ras dimers, establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane. We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this model in both basic and translational Ras biology.

Honokiol and magnolol (an isomer of honokiol) are small-molecule polyphenols isolated from the barks of Magnolia officinalis, which have been widely used in traditional Chinese and Japanese medicines. In the last decade, a variety of biological properties of honokiol and magnolol (e.g., anti-oxidativity, antitumor activity, anti-depressant activity, anti-inflammatory activity, neuroprotective activity, anti-diabetic activity, antiviral activity, and antimicrobial activity) have been reported. Meanwhile, certain mechanisms of action of some biological activities were also investigated. Moreover, many analogs of honokiol and magnolol were prepared by structural modification or total synthesis, and some exhibited very potent pharmacological activities with improved water solubility. Therefore, the present review will provide a systematic coverage on recent developments of honokiol and magnolol derivatives in regard to semisynthesis, total synthesis, and structure-activity relationships from 2000 up to now.