A5060410969- PARP inhibition in cancer therapy
- Glioma Diagnosis and Treatment
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- Brain Metastases and Treatment
- Protein Kinase Regulation and GTPase Signaling
- RNA Research and Splicing
- Microtubule and mitosis dynamics
- PI3K/AKT/mTOR signaling in cancer
- Histone Deacetylase Inhibitors Research
- Nuclear Structure and Function
- Cancer Research and Treatments
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Cancer, Hypoxia, and Metabolism
- MicroRNA in disease regulation
- Cholinesterase and Neurodegenerative Diseases
- Cardiac electrophysiology and arrhythmias
- Protein Degradation and Inhibitors
- Cancer Cells and Metastasis
- Radiopharmaceutical Chemistry and Applications
- Phagocytosis and Immune Regulation
- Cell death mechanisms and regulation
- Calpain Protease Function and Regulation
- Autophagy in Disease and Therapy
University of Southern California
2018-2024
Universidad Complutense de Madrid
2015-2021
Neurological Surgery
2021
Auranofin is an FDA-approved, gold-containing compound in clinical use for the oral treatment of rheumatoid arthritis and has been recently granted by regulatory authorities due to its antiprotozoal properties.A reprofiling strategy was performed with a Streptococcus pneumoniae phenotypic screen proprietary library compounds, consisting both FDA-approved unapproved bioactive compounds. Two different multiresistant S. strains were employed sepsis mouse model infection. In addition, MRSA...
Blockade of Ras activity by inhibiting its post-translational methylation catalyzed isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity inhibitors precluded clinical validation this approach. In work we report potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against other enzymes involved in modifications Ras. Compound significantly impairs membrane association four isoforms, leading to...
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 its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of patients are limited, highlighting need new therapeutic strategies. Here, we validate enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as target with development series potent inhibitors this that...
Abstract Background The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability blood-brain barrier (BBB). NEO100 a high-purity version natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open BBB rodent...
Abstract Background Intracarotid injection of mannitol has been applied for decades to support brain entry therapeutics that otherwise do not effectively cross the blood–brain barrier (BBB). However, elaborate and high-risk nature this procedure kept its use restricted well-equipped medical centers. We are developing a more straightforward approach safely open BBB, based on intra-arterial (IA) NEO100, highly purified version natural monoterpene perillyl alcohol. Methods In vitro permeability...
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in progression. The poor prognosis GBM associated with high rate of recurrence, resistance to the standard care chemotherapy, temozolomide (TMZ). novel compound NEO212, conjugate TMZ perillyl alcohol (POH), has proven be 10-fold more cytotoxic glioma stem cells (GSC) than TMZ, active against TMZ-resistant...
Brain arteriovenous malformations (AVMs) are abnormal tangles of vessels where arteries and veins directly connect without intervening capillary nets, increasing the risk intracerebral hemorrhage stroke. Current treatments highly invasive often not feasible. Thus, effective noninvasive needed. We previously showed that AVM-brain endothelial cells (BECs) secreted higher VEGF (vascular growth factor) lower TSP-1 (thrombospondin-1) levels than control BEC; microRNA-18a (miR-18a) normalized...
Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, development new compounds that induce inhibition proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe antiangiogenic compound (22) inhibits under hypoxic conditions in breast cancer cells. Compound 22 blocks MAPK pathway, impairs cellular migration conditions, regulates set genes related to angiogenesis. These responses are mediated...
Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation Ras complexity and a dearth structural information. In regard, recent studies revealed the highly dynamic character surface existence transient pockets suitable for small-molecule binding, opening up new possibilities development modulators. Herein, novel inhibitor (compound 12) is described that selectively impairs mutated...
NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to alkylating temozolomide (TMZ). It undergoing preclinical development as therapeutic for brain-localized malignancies. The aim this study characterize metabolism and pharmacokinetic (PK) properties in models.We used mass spectrometry (MS) modified high-performance liquid chromatography identify quantitate its metabolites cultured glioblastoma cells,...
Abstract Excessive exposure to ultraviolet radiation (UVR) causes harmful effects on human skin. Pre‐exposure application of sunscreen can be protective, but not after damage already has occurred. There is a need for agents that applied post‐UVR repair the damage. We investigated novel compound, NEO400, appears meet this medicinal need. NEO400 was created by conjugating linoleic acid perillyl alcohol. UVR repeatedly administered skin mice over several weeks, where it caused typical signs UV...
Glioblastoma (GBM) is the most aggressive type of brain tumor with a high rate recurrence, and it often develops resistance over time to current standard care chemotherapy. Its highly invasive nature plays an essential role in progression recurrence. Glioma stem cells (GSCs) are subpopulation glioma resistant treatments considered responsible for
Two distinct series of the 3-amino-1,5-benzoxathiepin scaffold, derived from L-cysteine, were synthesized and evaluated for their anti-proliferative activity in breast cancer MDA-MB-231 MCF-7 cells, ovarian carcinoma SKOV-3 cell line. (3R)-Amino-3,4-dihydro-2H-1,5-benzoxathiepin [(R)-10] was diversified into two forms: (a) by incorporating different amino acids at its position 3, through an amide bond; (b) construction purine ring to give...
Glioblastoma (GBM) is a highly aggressive primary brain tumor with poor prognosis. Treatment temozolomide, standard of care for gliomas, usually results in drug resistance and recurrence. Therefore, there great need drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via carbamate bond form the rolipram-perillyl conjugate. We show here effective against both temozolomide-sensitive temozolomide-resistant glioma cells. Furthermore, different...
ABSTRACT Progerin is a mutant prelamin A variant that causes Hutchinson–Gilford progeria syndrome (HGPS, progeria), rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored experimental models, clinical trials shown very limited benefits HGPS patients. Here, we describe the development of UCM-13207, new potent inhibitor isoprenylcysteine carboxylmethyltransferase (ICMT) reduces progerin nuclear accumulation...
Background: RAS overexpression and activation is a common leukemogenic mechanism in acute myeloid leukemia (AML), which characterized by HRAS, NRAS KRAS mutations. However, after several decades of continuous research efforts, direct inhibition with small molecules still remains current challenge. Instead, interference the enzymes involved post‐translational modification could be an alternative. Among these enzymes, isoprenylcysteine carboxylmethyltransferase (ICMT) deserves special...
<p>Acute and Chronic toxicity of NEO214.</p>
<p>Human astrocytes produce TRAIL.</p>
<p>Behavior study after Rolipram or NEO214 treatment.</p>