Person: Khiar Fernández, Nora
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First Name
Nora
Last Name
Khiar Fernández
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Química Orgánica
Area
Química Orgánica
Identifiers
3 results
Search Results
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Item Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice(Journal of Medicinal Chemistry, 2022) Khiar Fernández, Nora; Zian, Debora; Vázquez Villa, Henar; Martínez, R. Fernando; Escobar Peña, Andrea; Foronda Sainz, Román; Ray, Manisha; Puigdomenech Poch, Maria; Cincilla, Giovanni; Sánchez Martínez, Melchor; Kihara, Yasuyuki; Chun, Jerold; López Vales, Rubèn; López Rodríguez, María L.; Ortega Gutiérrez, SilviaSpinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI.Item Validation of the LPA2 receptor as new therapeutic target for the treatment spinal of cord injury(2023) Khiar Fernández, Nora; López Rodríguez, María Luz; Ortega Gutiérrez, Silvia; Vázquez Villa, María Del HenarSpinal cord injury (SCI) involves a permanent damage to the spinal cord which can lead into permanent neurological impairments that have an enormous impact in the quality of life of affected people. The pathology of SCI is multifaceted, complex, and yet to be fully understood. Once produced the primary injury responsible of the SCI, normally related with a traumatic impact or with the appearance of a tumor, infections or degenerative processes, the only pharmacological option is to treat the secondary damage and to limit the disruption of spinal connectivity. However, there is no effective clinical treatment for SCI, since current therapies are limited to surgical decompression and the administration of anti-inflammatory drugs. Hence, it is clear that new pharmacological approaches are needed to improve SCI patient condition. In this regard, inhibition of the type 2 lysophosphatidic acid (LPA2) receptor signaling has recently emerged as a new therapeutic option to limit the SCI associated damage. However, the validation of this approach has been limited by the lack of antagonists of the LPA2 receptor. In this regard, only one compound (Cpd35, Figure 1) has been characterized as a potent (IC50 value at LPA2 of 0.017 μM) and selective LPA2 antagonist (IC50 values >50 μM at LPA1 and LPA3 receptors)...Item 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 LuzHutchinson–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.