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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Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.
Progerin is a mutant prelamin A variant that causes Hutchinson–Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria.
Background:RAS overexpression and activation is a common leukemogenic mechanism in acute myeloid leukemia (AML), which is characterized by HRAS, NRAS and KRAS mutations. However, after several decades of continuous research efforts, RAS direct inhibition with small molecules still remains a current challenge. Instead, interference with the enzymes involved in the post‐translational modification of RAS could be an alternative. Among these enzymes, the inhibition of isoprenylcysteine carboxylmethyltransferase (ICMT) deserves special attention considering that its inactivation blocks RAS proper localization and activity, and ameliorates phenotypes of RAS‐induced malignancies in vivo.Aims:Our working hypothesis will test the efficacy of a novel ICMT inhibitor (UCM‐1336) against RAS‐driven tumors, such as NRAS mutant AML.Methods:In order to identify new ICMT inhibitors, we carried out a screening of our in‐house library and performed docking studies to optimize the hit initially discovered. We have used confocal and immunofluorescence microscopy to confirm that the optimal compound (UCM‐1336) delocalizes all RAS‐isoforms (HRAS, NRAS and KRAS) from the membrane. Moreover, we analyzed UCM‐1336 effect in apoptosis and RAS downstream pathway (RAS, MEK and AKT) by western blot. Furthermore, in vitro MTT viability validation of six RAS‐dependent cell lines and controls (2 fibroblasts cell lines) was performed. Finally, we developed an in vivo assay in xenograft NSG mice transplanted with 1 million IV injected AML HL‐60 NRAS dependent cells, and after 1 week of engraftment the mice were treated with UCM‐1336 (25 mg/kg, intraperitoneally) for 15 days (3 cycles of 5 days of treatment followed by 2 days of rest). Results were analyzed by Kaplan‐Meier survival curve and bone marrow IHC of HL60 positive cells (human CD45 positive).Results:Initial high‐throughput screening followed by compound optimization strategies led to the identification of the new ICMT inhibitor UCM‐1336. Treatment of PC‐3 cells with 5 μM of UCM‐1336 significantly induced RAS mislocalization. Moreover, UCM‐1336 treatment decreased active RAS (GTP‐bound complex), the activity of its downstream MEK/ERK and PI3K/AKT signaling pathways, and activated autophagy and apoptosis (LC‐3 and PARP1 expression and CASP3 activity). In vitro, UCM‐1336 inhibited viability of RAS‐driven cancer cell lines (PANC1, MIA‐PaCa‐2, MDA‐MB‐231, SW620, SK‐Mel‐173 and HL60) with IC50 values between 2–12 uM. In addition, it showed selectivity versus control fibroblasts (>50 uM, NIH3T3 and 142BR). Finally, the treatment of NSG HL60 transplanted xenograft mice with UCM‐1336 led to a significant delay in tumor development and death and decreased HL60 infiltration in bone marrow compared to vehicle administration.Summary/Conclusion:UCM‐1336 is a novel ICMT inhibitor with capacity to kill RAS‐driven tumor cells in vitro and in vivo such as acute myeloid leukemia KRAS, HRAS and NRAS‐driven tumors.imageThis work was supported by grants from the Spanish MINECO (SAF2016–78792‐R, SAF2017–89672‐R).
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