Person:
Marcos Ramiro, Beatriz

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First Name
Beatriz
Last Name
Marcos Ramiro
URI
https://hdl.handle.net/20.500.14352/84517
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
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2019 - 201912020 - 20211
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    A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia
    (Journal of Medicinal Chemistry, 2019) Marín Ramos, Nagore Isasbel; Balabasquer Peña, Moisés; Ortega Nogales, Francisco Jesús; Torrecillas, Iván R.; Gil Ordoñez, Ana; Marcos Ramiro, Beatriz; Aguilar Garrido, Pedro; Cushman, Ian; Romero, Antonio; Medrano, Francisco J.; Gajate Fraile, Consuelo; Mollinedo García, Faustino; Philips, Mark R.; Campillo, Mercedes; Gallardo Delgado, Miguel; Martín Fontecha, Mar; López Rodríguez, María Luz; Ortega Gutiérrez, Silvia
    Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
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    Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson−Gilford Progeria Syndrome
    (ACS Central Science, 2021) Marcos Ramiro, Beatriz; Gil Ordóñez, Ana; Marín Ramos, Nagore I.; Ortega Nogales, Francisco J.; Balabasquer, Moisés; Gonzalo, Pilar; Ortega Gutiérrez, Silvia; Khiar Fernández, Nora; Rolas, Loic; Barkaway, Anna; Nourshargh, Sussan; Andrés, Vicente; Martín-Fontecha Corrales, María Del Mar; López Rodríguez, María Luz
    Hutchinson–Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the LmnaG609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.