RESUMEN
Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology.
Asunto(s)
Proteína bcl-X/antagonistas & inhibidores , Humanos , Modelos Moleculares , Unión ProteicaRESUMEN
Targeted covalent inhibition of disease-associated proteins has become a powerful methodology in the field of drug discovery, leading to the approval of new therapeutics. Nevertheless, current approaches are often limited owing to their reliance on a cysteine residue to generate the covalent linkage. Here we used aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain, and generated to our knowledge the first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies. These covalent binders exhibited improved potency in comparison to noncovalent congeners, as demonstrated in biochemical and cell-based assays. We identified Lys234 as the residue involved in covalent modification, via point mutation. The covalent binders discovered in this study will serve as useful starting points for the development of Mcl-1 therapeutics and probes to interrogate Mcl-1-dependent biological phenomena.
Asunto(s)
Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Lisina/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Ácidos Borónicos/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Concentración de Iones de Hidrógeno , Lisina/metabolismo , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Relación Estructura-ActividadRESUMEN
Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and C-N cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance, and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centered radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.
RESUMEN
A visible-light-promoted iridium photoredox and nickel dual-catalyzed cross-coupling procedure for the formation C-N bonds has been developed. With this method, various aryl amines were chemoselectively cross-coupled with electronically and sterically diverse aryl iodides and bromides to forge the corresponding C-N bonds, which are of high interest to the pharmaceutical industries. Aryl iodides were found to be a more efficient electrophilic coupling partner. The coupling reactions were carried out at room temperature without the rigorous exclusion of molecular oxygen, thus making this newly developed Ir-photoredox/Ni dual-catalyzed procedure very mild and operationally simple.
RESUMEN
In order to achieve reproducibility during iridium-photoredox and nickel dual-catalyzed sp(3)-sp(2) carbon-carbon bond-forming reactions, we investigated the role that molecular oxygen (O2), solvent and light-source (CF lamp or blue LED) play in a variety of Ir-photoredox mediated transformations. The presence of O2 was discovered to be important for catalyst activation when air-stable Ni(II) precatalysts were used in DMF under CF lamp irradiation; however, O2 was not required for catalysis when conducted with Ni(COD)2 in the same reaction system. O2 is believed to promote rapid reduction of the Ni(II) precatalyst by Ir(II) to Ni(0). In addition to O2, the effects that solvent and light-source have on the dual-catalyzed decarboxylative cross-coupling reactions will be discussed. These findings have enabled us to develop a more robust dual-catalyzed decarboxylative cross-coupling protocol.
Asunto(s)
Carbono/química , Iridio/química , Níquel/química , Oxígeno/química , Catálisis , Luz , Estructura Molecular , Oxidación-Reducción , Procesos Fotoquímicos , Reproducibilidad de los Resultados , Solventes/químicaRESUMEN
The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
Asunto(s)
Diseño de Fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Proteínas Inhibidoras de la Apoptosis/síntesis química , Proteínas Inhibidoras de la Apoptosis/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
Asunto(s)
Aminas/síntesis química , Diseño de Fármacos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Proteínas Mitocondriales/química , Piperidinas/síntesis química , Aminas/química , Aminas/farmacología , Proteínas Reguladoras de la Apoptosis , Biomimética , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The direct ß-functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of ß-C-H bonds in these motifs. Herein, we demonstrate the ß-functionalization of saturated aza-heterocycles enabled by a two-step organic photoredox catalysis approach. Initially, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C-C, C-O, and C-N aza-heterocycles at the ß-position.
RESUMEN
Minimizing the number and duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes or drug candidates is an ongoing challenge in biomedical research. Small structure modifications to hit or lead compounds can have meaningful impacts on pharmacological profiles due to significant effects on molecular and physicochemical properties and intra- and intermolecular interactions. Rapid pharmacological profiling of an efficiently prepared series of positional analogues stemming from the systematic exchange of methine groups with heteroatoms or other substituents in aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing design cycles (e.g., exchange of aromatic or heteroaromatic CH groups with N atoms or CF, CMe, or COH groups). In this Perspective, positional analogue scanning is shown to be an effective strategy for multiparameter optimization in drug design, whereby substantial improvements in a variety of pharmacological parameters can be achieved.
Asunto(s)
Diseño de Fármacos , Compuestos Heterocíclicos/química , Hidrocarburos Aromáticos/química , Animales , Flúor/química , Compuestos Heterocíclicos/metabolismo , Humanos , Hidrocarburos Aromáticos/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Metaloproteinasas de la Matriz/química , Metaloproteinasas de la Matriz/metabolismo , Microsomas/metabolismo , Nitrógeno/química , Relación Estructura-ActividadRESUMEN
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Mutación , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Administración Oral , Animales , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Ratas , Relación Estructura-Actividad , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Tiazoles/farmacología , Células 3T3 , Amidas/química , Amidas/farmacocinética , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Femenino , Humanos , Ratones , Ratones Desnudos , Ratas , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Animales , Bortezomib/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Mieloma Múltiple/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Ratas , Ratas Desnudas , Sulfonamidas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins. AREAS COVERED: This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists. EXPERT OPINION: In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space - for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles - tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.
Asunto(s)
Materiales Biomiméticos/farmacología , Diseño de Fármacos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Oligopéptidos/química , Patentes como Asunto , Transducción de Señal/efectos de los fármacosRESUMEN
A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
Asunto(s)
Alquinos/farmacología , Antineoplásicos/farmacología , Materiales Biomiméticos/farmacología , Descubrimiento de Drogas , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Oligopéptidos/farmacología , Alquinos/síntesis química , Alquinos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dimerización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Conformación Molecular , Neoplasias/patología , Oligopéptidos/síntesis química , Oligopéptidos/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Quinazolinas/síntesis química , Animales , Humanos , Masculino , Melanoma/tratamiento farmacológico , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.