Drug targeting opportunities en route to Ras nanoclusters

Pavic, Karolina; Chippalkatti, Rohan; Abankwa, Daniel

doi:10.1016/bs.acr.2021.07.005

Cited by 9 publications

(9 citation statements)

References 149 publications

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“…Inhibitors of Ras membrane anchorage are expected to shut down Ras-signaling output . For instance, farnesyl-transferase inhibitors that block the enzyme-mediating Ras farnesylation are now applied with some success in HRAS mutant head and neck cancers .…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of Ras membrane targeting remains a promising strategy for inhibitor development. , The trafficking chaperone PDE6D (or PDEδ) has been proposed as a surrogate drug target in KRAS mutant cancers . PDE6D possesses a hydrophobic pocket, which can bind to one or even two prenyl moieties, thus having a cargo spectrum that comprises farnesylated or geranylgeranylated Ras and Rho family proteins as well as Rab proteins. , Only proteins that are not in addition palmitoylated in the vicinity of the prenylated cysteine are accepted as cargo, making mono- and dual-palmitoylated N-Ras, K-Ras4A, and H-Ras effectively worse PDE6D cargo in cells than K-Ras4B (hereafter K-Ras) .…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of Ras membrane targeting remains a promising strategy for inhibitor development. 5 , 6 The trafficking chaperone PDE6D (or PDEδ) has been proposed as a surrogate drug target in KRAS mutant cancers. 7 PDE6D possesses a hydrophobic pocket, which can bind to one or even two prenyl moieties, thus having a cargo spectrum that comprises farnesylated or geranylgeranylated Ras and Rho family proteins as well as Rab proteins.…”

Section: Introductionmentioning

confidence: 99%

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An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

Kaya,

Schaffner-Reckinger,

Manoharan

et al. 2024

J. Med. Chem.

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The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of KRAS mutant and PDE6D-dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

Kaya,

Schaffner-Reckinger,

Manoharan

et al. 2024

J. Med. Chem.

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“…Currently, less than a dozen proteins are known that can modulate Ras nanoclustering 17 . These proteins do not share any structural or functional similarities, suggesting that their mechanisms of nanocluster modulation are diverse.…”

Section: Introductionmentioning

confidence: 99%

Identification of an H-Ras nanocluster disrupting peptide

Manoharan,

Steffen,

Pavic

et al. 2023

Preprint

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The Ras-MAPK pathway is critical to regulate cell proliferation and differentiation. Its dysregulation is implicated in the onset and progression of numerous types of cancers. To be active, Ras proteins are membrane anchored and organized into nanoclusters, which realize high-fidelity signal transmission across the plasma membrane. Nanoclusters therefore represent potential drug targets. However, targetable protein components of signalling nanoclusters are poorly established.We previously proposed that the nanocluster scaffold galectin-1 (Gal1) enhances H-Ras nanoclustering by stabilizing stacked dimers of H-Ras and Raf via a direct interaction of dimeric Gal1 with the Ras binding domain (RBD) in particular of B-Raf. Here, we provide further supportive evidence for this model. We establish that the B-Raf preference emerges from divergent regions of the Raf RBDs that were proposed to interact with Gal1. We then identify the L5UR peptide, which disrupts this interaction by binding with low micromolar affinity to the B-Raf-RBD. Its 23-mer core fragment is thus sufficient to interfere with Gal1-enhanced H-Ras nanocluster, reduce MAPK-output and cell viability inHRAS-mutant cancer cell lines.Our data therefore suggest that the interface between Gal1 and the RBD of B-Raf can be targeted to disrupt Gal1-enhanced H-Ras nanoclustering. Collectively, our results support that Raf-proteins are integral components of active Ras nanoclusters.

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“…Ras membrane association is required for its activity, and membrane affinity is mediated by C- terminal lipid modifications of Ras by farnesyltransferase and palmitoyltransferases (Pavic et al , 2022). Farnesylation also mediates binding of Ras to trafficking chaperones, such as PDE6D and calmodulin, which facilitate its diffusion, followed by trapping on secretory organelles, and subsequent vesicular transport to the plasma membrane (Schmick et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation

Chippalkatti,

Parisi,

Kouzi

et al. 2023

Preprint

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The Ras-MAPK pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While the impact of Ras on proliferation is typically assessed on various cancer cell lines, it is poorly established how Ras affects cellular differentiation.Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that the Pax7+ progenitors divide asymmetrically to replenish the major pool of transit amplifying cells that are ready to differentiate. Intriguingly, Ras isoforms have distinct roles in the differentiating culture, where K-Ras is more important than N-Ras to maintain the progenitor pool, and H-Ras is significant for the expansion of differentiated cells. While overexpression of wild-type K-Ras increases the fraction of differentiated cells at the expense of transit amplifying cells, all oncogenic mutants block further differentiation of transit amplifying cells. Interestingly, RASopathy associated mutants display distinct phenotypes. Notably variants that are also NF1-GAP resistant block differentiation as their oncogenic counterparts, albeit less. Profiling of targeted Ras-pathway drugs on oncogenic Ras mutants reveals their distinct abilities to restore normal differentiation as compared to triggering cell death. Interestingly, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTORC1 inhibitor rapamycin broadly suppressed differentiation.We expect that this quantitative assessment of the impact of Ras-pathway mutans and drug treatments on cellular differentiation will provide significant new insights into Ras biology and Ras-driven diseases.

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Drug targeting opportunities en route to Ras nanoclusters

Cited by 9 publications

References 149 publications

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth

Identification of an H-Ras nanocluster disrupting peptide

RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation

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