RESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.
Asunto(s)
Antiparkinsonianos/farmacología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Receptor alfa X Retinoide/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Encéfalo/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Dopamina/genética , Estabilidad de Medicamentos , Humanos , Masculino , Ratones Endogámicos BALB C , Terapia Molecular Dirigida , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/agonistas , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Multimerización de Proteína , Ratas , Receptor alfa X Retinoide/agonistas , Receptor alfa X Retinoide/química , Receptor alfa X Retinoide/genéticaRESUMEN
The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antibody for active tumour targeting.SAP was evaluated in silico and in vitro in order to verify target engagement (e.g., VEGFR2). Pharmacokinetic and biodistribution parameters were determined in mice using LC-MS/MS. SAP efficacy was tested in two breast cancer xenograft and two syngeneic animal models and pharmacodynamic evaluation was accomplished using phosphokinase assays and immunohistochemistry. Cardiac and blood toxicity of SAP were also monitored.SAP retained the antiangiogenic and cytotoxic properties of the parental molecule with an increased blood exposure and tumor accumulation compared to sunitinib. SAP proved efficacious in all animal models. Tumors from SAP treated animals had significantly decreased Ki-67 and CD31 markers and reduced levels of phosphorylated AKT, ERK and S6 compared to vehicle treated animals. In mice dosed with SAP there was negligible hematotoxicity, while cardiac function measurements showed a reduction in the percentage left ventricular fractional shortening compared to vehicle treated animals.In conclusion, SAP is a novel rationally designed conjugatable small antiangiogenic molecule, efficacious in preclinical models of breast cancer.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Indoles/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de la Angiogénesis/síntesis química , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Indoles/síntesis química , Indoles/química , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/patología , Oxindoles , Pirroles/química , Pirroles/uso terapéutico , Sunitinib , Carga Tumoral , Microambiente Tumoral , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys(6)]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (â¼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation.