Latest Advances Towards Ras Inhibition: A Medicinal Chemistry Perspective

Sautier, Brice; Nising, Carl F.; Wortmann, Lars

doi:10.1002/anie.201608270

Cited by 14 publications

(8 citation statements)

References 59 publications

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“…These interesting discoveries suggest that ARS-853 could be combined with other inhibitors of upstream signaling pathways to disrupt signaling via K-Ras G12C and achieve clinical efficacy. The compatibility of ARS-853 with in vivo use has yet to be confirmed, since it has low metabolic stability and the potential to engage in offtarget effects [81]. Despite the need for further optimization, the creation of ARS-853 represents a significant step forward and can be used as a robust benchmark for the design of future small molecule inhibitors.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Ras and Rap1: A tale of two GTPases

Shah

Brock

et al. 2019

Seminars in Cancer Biology

149

112

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Ras oncoproteins play pivotal roles in both the development and maintenance of many tumor types. Unfortunately, these proteins are difficult to directly target using traditional pharmacological strategies, in part due to their lack of obvious binding pockets or allosteric sites. This obstacle has driven a considerable amount of research into pursuing alternative ways to effectively inhibit Ras, examples of which include inducing mislocalization to prevent Ras maturation and inactivating downstream proteins in Ras-driven signaling pathways. Ras proteins are archetypes of a superfamily of small GTPases that play specific roles in the regulation of many cellular processes, including vesicle trafficking, nuclear transport, cytoskeletal rearrangement, and cell cycle progression. Several other superfamily members have also been linked to the control of normal and cancer cell growth and survival. For example, Rap1 has high sequence similarity to Ras, has overlapping binding partners, and has been demonstrated to both oppose and mimic Ras-driven cancer phenotypes. Rap1 plays an important role in cell adhesion and integrin function in a variety of cell types. Mechanistically, Ras and Rap1 cooperate to initiate and sustain ERK signaling, which is activated in many malignancies and is the target of successful therapeutics. Here we review the role activated Rap1 in ERK signaling and other downstream pathways to promote invasion and cell migration and metastasis in various cancer types.

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Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Ras and Rap1: A tale of two GTPases

Shah

Brock

et al. 2019

Seminars in Cancer Biology

149

112

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“…Recent strategies to directly inhibit RAS have focused on ( i ) targeting Cys12 of the oncogenic mutant KRAS G12C with covalent inhibitors, ( ii ) RAS–effector interactions to disrupt downstream signaling, or ( iii ) inhibiting the RAS–GEF interactions to prevent reloading with GTP (10). While the first two strategies have seen recent encouraging successes (11–14), targeting the RAS–GEF interactions has not yet generated potent inhibitors. Furthermore, whether mutant RAS proteins require GEF activity for full activation remains to be fully explored and may differ depending on the specific mutation (15).…”

mentioning

confidence: 99%

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction

Hillig

Sautier

Schroeder

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

309

322

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SignificanceMutants of RAS are major oncogenes and occur in many human cancers, but efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have failed so far. We therefore focused on SOS1, the guanine nucleotide exchange factor (GEF) and activator of RAS. A combination of high-throughput and fragment screening resulted in the identification of nanomolar SOS1 inhibitors, which effectively down-regulate active RAS in tumor cells. In cells with wild-type KRAS, we observed complete inhibition of the RAS-RAF-MEK-ERK pathway. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of phospho-ERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a viable approach for targeting RAS-driven tumors.

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“…Another approach has led to rigosertib (currently in phase III clinical trials for myelodisplastic syndrome) which provide its antiproliferative effect through Ras-RBD interaction inhibition. Despite not targeting Ras directly, the RBD-binding properties of the rigosertib result in a dose-dependent inhibition of Ras-RAF, Ras-PI3Kα, β, γ, and Ras-Ral-GDS [38].…”

Section: Ras Proteinmentioning

confidence: 99%

Highlights on Specific Biological Targets; Cyclin-Dependent Kinases, Epidermal Growth Factor Receptors, Ras Protein, and Cancer Stem Cells in Anticancer Drug Development

Hawash

2019

Drug Res (Stuttg)

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Cancer is the second leading cause of death in worldwide, because of that we need a great effort to discover, determine and understand the main pathways and mechanism of action of new novel anticancer drugs, which highly selective on the cancerous cells over the normal cells. The traditional approaches to the treat cancer depend on surgery, radiotherapy, and chemotherapy, according to the medicinal reports the chemotherapy is still the main procedure in the cancer cure or treatment till nowadays, and it is one of the main factors that drops the mortality of cancer in the last years. In the past decades the chemotherapeutic agents were used in the cancer treatment without clear understand on which target, protein, or enzyme that is working, and it was making the inhibition on the whole family of enzymes or receptors which lead to high toxicity and side effects, but nowadays the anticancer agents work with high selectivity on specific subtype of clear targets, and these targets usually present in high percentage in the cancerous cells. In this review article we will summarize some of these specific targets for anticancer drugs like Cyclin-dependent kinases (CDKs), epidermal growth factor receptors (EGFR), Ras protein, and Cancer stem cells, finally, we will mention some anticancer drugs which approved by FDA in 2018 which work on specific targets.

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Latest Advances Towards Ras Inhibition: A Medicinal Chemistry Perspective

Cited by 14 publications

References 59 publications

Ras and Rap1: A tale of two GTPases

Ras and Rap1: A tale of two GTPases

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction

Highlights on Specific Biological Targets; Cyclin-Dependent Kinases, Epidermal Growth Factor Receptors, Ras Protein, and Cancer Stem Cells in Anticancer Drug Development

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