Putting the brakes on KRAS-G12C nucleotide cycling

Shipman, Lydia

doi:10.1038/nrd.2016.40

Cited by 6 publications

(4 citation statements)

References 2 publications

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“…Mechanistically, it was discovered that ARS-853 preferentially binds to GDP-bound K-Ras G12C [78,79] -and that K-Ras G12C still rapidly cycles between active and inactive forms. These findings challenge the view that all activating mutations in KRAS function like the G12D mutation and lock Ras in the active state (i.e., the GTP-bound form) [80]. Adding to these observations, ARS-853 was also found to reduce the interaction between K-Ras G12C and Sos, thus reducing Sos mediated nucleotide exchange [78].…”

Section: Small Molecule Inhibitorsmentioning

confidence: 83%

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: 83%

Ras and Rap1: A tale of two GTPases

Shah

Brock

et al. 2019

Seminars in Cancer Biology

149

112

View full text Add to dashboard Cite

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“…They found that ARS-853 could only interact with KRAS G12C in the GDP-bound state by comparing the therapeutic effect of ARS-853 on cells with KRAS G12C in the GTP-bound state or GDP-bound state. The nucleotide state of KRAS G12C is in dynamic flux, and ARS-853 fully integrates with the protein and inhibit its activation by modulating the upstream signaling factor [ 13 , 14 ]. The disadvantages of ARS-853 are its poor stability in plasma (t 1/2 < 20 min) and its low bioavailability after oral administration in mice (F < 2%).…”

Section: Early Studiesmentioning

confidence: 99%

The Research Progress of Direct KRAS G12C Mutation Inhibitors

Yang

Fang

2021

Pathol. Oncol. Res.

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Section: Allosteric Inhibition Of Ras By Targeting Its Allosteric Smentioning

confidence: 99%

“…25,156,157 Collectively, these data suggest that targeting the allosteric site, S-IIP, to stabilize the inactive, GDP-bound Ras G12C provides a framework for generating new anti-Ras therapeutics. 158 4.4 Helix a1, switch I, and strand b2 Large-scale MD simulations of K-Ras4B Q61H -GTP found that the conformational ensemble of K-Ras4B Q61H -GTP contained active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free states. 159 Rational design of small molecule inhibitors that especially interact with the inactive states of GTP-bound Ras and shift the conformational ensemble towards the inactive states can inhibit Ras signaling.…”

Section: Switch II Pocket (S-iip)mentioning

confidence: 99%

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

et al. 2016

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Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras–effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.

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Putting the brakes on KRAS-G12C nucleotide cycling

Cited by 6 publications

References 2 publications

Ras and Rap1: A tale of two GTPases

Ras and Rap1: A tale of two GTPases

The Research Progress of Direct KRAS G12C Mutation Inhibitors

Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

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