Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling

Yelland, T.; Garcia, Esther Perez; Parry, Charles; Kowalczyk, Dominika; Wojnowska, Marta; Gohlke, Andrea; Zalar, Matja; Cameron, Kenneth; Goodwin, Gillian; Yu, Qing; Zhu, Pengcheng; ElMaghloob, Yasmin; Pugliese, Angelo; Archibald, Lewis J.; Jamieson, Andrew G.; Chen, Yong Xiang; McArthur, Duncan; Bower, Justin; Ismail, Shehab

doi:10.1021/acs.jmedchem.1c01265

Cited by 10 publications

(24 citation statements)

References 50 publications

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“…Moreover, the combination of C14 and P8 caused a 99% reduction in the clonogenicity of PDAC cells. The structural basis for KRas4B/PDE6δ complex formation and simultaneous binding of molecules has been recently demonstrated ( Yelland et al, 2022 ). This study confirmed our previous finding that sequestering this complex in the cytosol prevents KRas activation at the plasma membrane and downstream ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer

Briseño-Díaz,

Schnoor,

Bello-Ramirez

et al. 2023

Life Sci. Alliance

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Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.

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Section: Discussionmentioning

confidence: 99%

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer

Briseño-Díaz,

Schnoor,

Bello-Ramirez

et al. 2023

Life Sci. Alliance

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“…Another complication of PDE6D as a drug target is its intrinsically broad cargo spectrum. , Therefore, its inhibition will affect not only K-Ras and thus KRAS mutant cancer cells but also a host of PDE6D cargos. Finally, the ontogenetic role of PDE6D may be worth considering.…”

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) . Cargo affinity is critically modulated by the four residues upstream of the prenylated cysteine.…”

Section: Introductionmentioning

confidence: 99%

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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“…Similar responses were reported for Deltarasin, an effect attributed to active function and efflux by ABC transporter proteins although we cannot exclude other mechanisms in Tsc2-null MEF cells ( Zimmermann et al, 2013 ). At least for cancer cell lines, it is known that PDEδ is highly expressed up to single digit micromolar ranges ( Yelland et al, 2022 ). Hence, equally high concentrations of PDEδ inhibitors are needed to interfere with the interaction of PDEδ and its client proteins.…”

Section: Discussionmentioning

confidence: 99%

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells

Armijo

Escalona²,

Peña³

et al. 2022

Front. Pharmacol.

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Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb’s farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

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Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling

Cited by 10 publications

References 50 publications

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer

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

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells

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