{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:13:03Z","timestamp":1753891983334,"version":"3.41.2"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1201215"],"award-info":[{"award-number":["1201215"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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\u2019s farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDE\u03b4. Recently, the use of PDE\u03b4 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 PDE\u03b4 inhibition on the Rheb\/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDE\u03b4 inhibitor, called Deltasonamide 1, in <jats:italic>Tsc2<\/jats:italic>-<jats:italic>null<\/jats:italic> MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDE\u03b4 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 <jats:italic>Tsc2-null<\/jats:italic> MEFs but has less effect on <jats:italic>Tsc2-wild type<\/jats:italic> MEFs viability. This work proposes the pharmacological PDE\u03b4 inhibition as a new approach to target the abnormal Rheb\/mTORC1 activation in Tuberous Sclerosis Complex cells.<\/jats:p>","DOI":"10.3389\/fphar.2022.912688","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T07:47:41Z","timestamp":1655970461000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Blocking the Farnesyl Pocket of PDE\u03b4 Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Marisol Estrella","family":"Armijo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilia","family":"Escalona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Farias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Violeta","family":"Morin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bert Matthias","family":"Klebl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxana","family":"Pincheira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariel Fernando","family":"Castro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.12688\/f1000research.22367.1","article-title":"Coordination of Rheb Lysosomal Membrane Interactions with mTORC1 Activation","volume":"9","author":"Angarola","year":"2020","journal-title":"F1000Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1002\/ijc.29707","article-title":"Rheb Signaling and Tumorigenesis: MTORC1 and New Horizons","volume":"138","author":"Armijo","year":"2016","journal-title":"Int. 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