RESUMEN
Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD+ to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (K d: 0.016 µM) and cellular (IC50: 0.027 µM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.
RESUMEN
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
Asunto(s)
Antineoplásicos/química , Isoindoles/química , Piperidinas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoindoles/administración & dosificación , Isoindoles/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temozolomida , Neoplasias de la Mama Triple NegativasRESUMEN
Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Adenosina Trifosfatasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HCT116 , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Proteína que Contiene ValosinaRESUMEN
We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
Asunto(s)
Antineoplásicos/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Janus Quinasa 2/metabolismo , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
INTRODUCTION: Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects. This later development of these drugs should make it possible, in principle, to selectively target neoplastic vs healthy cells, thus realizing the Ehrlich's magic bullet concept of a personalized and tailored cure of diseases. AREAS COVERED: This review is designed to provide the readers with a brief summary and an update on PARP inhibitors in the oncology field, by covering the recent patent literature (2010 - 2012: and Questel Intellectual Property Portal [QPat] database search). EXPERT OPINION: Presently, along with a number of preclinical candidates, there are eight PARP inhibitors in the clinic as either single agents or in combination with various chemotherapy and radiotherapy regimens. The tremendous efforts underneath those results testify the high interest on the target. The investigation and understanding of the cross-reactivity among members of the PARPs family as well as a deeper knowledge of their biological functions may lead to a more profound characterization of the PARP inhibitor's profile. This, in turn, will cast additional light on this exciting approach in treating cancer.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Control de Medicamentos y Narcóticos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Patentes como Asunto , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Triazoles/farmacología , Adenosina Trifosfatasas/química , Regulación Alostérica , Proteínas de Ciclo Celular/química , Humanos , Neoplasias/patología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Proteína que Contiene ValosinaRESUMEN
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S, [(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridonas/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Perros , Descubrimiento de Drogas , Humanos , Espectroscopía de Resonancia Magnética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridonas/química , Piridonas/farmacocinética , Ratas , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Relación Estructura-ActividadRESUMEN
Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridonas/síntesis química , Pirroles/síntesis química , Secuencia de Aminoácidos , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Furanos/síntesis química , Furanos/química , Furanos/farmacología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Proteínas Serina-Treonina Quinasas/química , Piridonas/química , Piridonas/farmacología , Pirroles/química , Pirroles/farmacología , Homología de Secuencia de Aminoácido , Relación Estructura-ActividadRESUMEN
The combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent member is combretastatin A-4, and this compound together with a phosphate pro-drug form have already progressed through into clinical trails for the treatment of solid tumours. What makes this class of compounds rather more interesting than other anti-mitotic agents is that they are also angiogenesis inhibitors, and are being evaluated for their efficacy in the treatment of diabetic retinopathy which is the biggest single cause of blindness They are thus of considerable contemporary interest.