A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

Marín-Ramos, Nagore I.; Balabasquer, Moisés; Ortega-Nogales, Francisco J.; Torrecillas, Iván R.; Gil-Ordóñez, Ana; Marcos‐Ramiro, Beatriz; Aguilar-Garrido, Pedro; Cushman, Ian; Romero, Antonio; Medrano, F.J.; Gajate, Consuelo; Mollinedo, Faustino; Philips, Mark R.; Campillo, M.; Gallardo, Miguel; Martín‐Fontecha, Mar; López-Rodrı́guez, Marı́a L.; Ortega-Gutiérrez, Sílvia

doi:10.1021/acs.jmedchem.9b00145

Cited by 33 publications

(16 citation statements)

References 43 publications

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“…Our findings suggested that the 3-amino- N -phenylpropanamide moiety as well as the n -octyl chain of compound 1 were key elements for interaction with ICMT. 20 Accordingly, we envisioned that the phenyl group could be further explored for optimizing cellular viability without significantly compromising ICMT inhibition ( Figure 1 a). This focused library was synthesized as detailed in the Supporting Information .…”

Section: Resultsmentioning

confidence: 99%

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson–Gilford Progeria Syndrome

et al. 2021

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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 Lmna G609G/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.

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Section: Resultsmentioning

confidence: 99%

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson–Gilford Progeria Syndrome

et al. 2021

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“…Targeting the downstream RAS processing enzymes, namely, RCE1 and ICMT, is an effective approach to prevent the compensation of FTase inhibitors by GGTase in KRAS -mutant tumors. Inhibitors of ICMT, such as cysmethynil and UCM-1336, have been developed and have shown a great capability to reduce KRAS activity and impair the growth of KRAS -mutant cell lines [ 92 , 93 ]. However, the clinical data of ICMT inhibitors in patients with KRAS-mutant CRC are not yet available.…”

Section: Kras Targeting Therapy In Crcmentioning

confidence: 99%

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

et al. 2021

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Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

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“…The importance of carboxyl methylation for proper membrane localization has been already described for other CAAX proteins, such as Ras [52,53]. In addition, inhibition of ICMT has been described as a promising strategy to inactivate Ras by inducing its mislocalization from the cellular membrane [54][55][56]. In this context, the finding that genetic disruption of ICMT improved the phenotype in the ZMPSTE24 mouse model of progeria supported that a small molecule ICMT inhibitor could represent a new therapeutic strategy to address HGPS.…”

Section: Methylation Inhibitorsmentioning

confidence: 74%

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

Macicior

Marcos‐Ramiro

Ortega-Gutiérrez

2021

IJMS

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Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.

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A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

Cited by 33 publications

References 43 publications

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson–Gilford Progeria Syndrome

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson–Gilford Progeria Syndrome

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

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