RESUMEN
The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.
Asunto(s)
Sinergismo Farmacológico , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas Proto-Oncogénicas c-bcl-2 , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.
Asunto(s)
Antineoplásicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Antineoplásicos/farmacología , Hidrogenación , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidoresRESUMEN
BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.
Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.
RESUMEN
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.
RESUMEN
Aberrant gene activation driven by the histone acetyltransferases p300 and CREB binding protein (CBP) has been linked to several diseases, including cancers. Because of this, many efforts have been aimed toward the targeting of the closely related paralogues, p300 and CBP, but these endeavors have been exclusively directed toward noncovalent inhibitors. X-ray crystallography of A-485 revealed that both p300 and CBP possess a cysteine (C1450) near the active site, thus rendering covalent inhibition an attractive chemical approach. Herein we report the development of compound 2, an acrylamide-based inhibitor of p300/CBP that forms a covalent adduct with C1450. We demonstrated using mass spectrometry that compound 2 selectively targets C1450, and we also validated covalent binding using kinetics experiments and cellular washout studies. The discovery of covalent inhibitor 2 gives us a unique tool for the study of p300/CBP biology.
RESUMEN
In continuation of our previous research towards the discovery of potent, selective and drug-like Wee1 inhibitors, 2 novel series of biaryl heterocycles were designed, synthesized and evaluated. The new biaryl cores were designed to enable structure-activity exploration of substituents at C-8 or N-8 which were used for tuning compound properties and to improve compound profiles. The lead molecule 33 demonstrated a desirable pharmacokinetic profile and potentiated the anti-proliferative activity of irinotecan in vivo when dosed orally in the human breast MX-1 xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Compuestos Heterocíclicos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Humanos , Relación Estructura-ActividadRESUMEN
Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
Asunto(s)
Alcaloides/síntesis química , Productos Biológicos/síntesis química , Alcaloides/química , Productos Biológicos/química , Biomimética , Catálisis , Química Orgánica/métodos , Ciclización , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/química , Indoles/síntesis química , Indoles/química , Quinolinas/síntesis química , Quinolinas/química , Proyectos de Investigación , Estricnina/síntesis química , Estricnina/químicaRESUMEN
The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective α-enolation and α-carbooxidation of ketones.
RESUMEN
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Imidazoles/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Cristalografía por Rayos X/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Diseño de Fármacos , Péptido 1 Similar al Glucagón/química , Humanos , Hidrólisis , Imidazoles/farmacología , Concentración 50 Inhibidora , Macaca mulatta , Ratones , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Fosfato de Sitagliptina , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Diseño de Fármacos , Cobayas , Humanos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Piperidinas/química , Piperidinas/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Semivida , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Estructura Molecular , Piperidinas/sangre , Ratas , Relación Estructura-ActividadRESUMEN
A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
Asunto(s)
Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/química , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Triazoles/química , Animales , Inhibidores de Proteasas/síntesis química , Pirazinas/química , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
The asymmetric α-addition of relatively nonpolar hydrocarbon substrates, such as allyl and aryl groups, to aldehydes and ketones remains a largely unsolved problem in organic synthesis, despite the wide potential utility of direct routes to such products. We reasoned that well-established chiral amine catalysis, which activates aldehydes toward electrophile addition by enamine formation, could be expanded to this important reaction class by applying a single-electron oxidant to create a transient radical species from the enamine. We demonstrated the concept of singly occupied molecular orbital (SOMO) activation with a highly selective α-allylation of aldehydes, and we here present preliminary results for enantioselective heteroarylations and cyclization/halogenation cascades.
Asunto(s)
Aldehídos/química , Catálisis , Compuestos Orgánicos/química , Estereoisomerismo , Aminas/química , Ciclización , Halógenos/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/síntesis química , Fenilalanina/análogos & derivados , Inhibidores de Proteasas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Canales de Calcio Tipo L/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Proteínas Musculares/antagonistas & inhibidores , Músculo Esquelético/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5 , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Conejos , Canales de Sodio , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
L-454,560 is a potent phosphodiesterase 4 (PDE4) inhibitor which was identified as a development candidate for the treatment of asthma and chronic obstructive pulmonary disease (COPD). As part of the discovery of this compound, interspecies in vitro metabolism data was generated using liver microsomes and hepatocytes in order to understand the metabolic fate of the compound. In microsomes, metabolism of the 3-methyl-1,2,4-oxadiazole ring was the predominant pathway observed, including ring cleavage. In rat hepatocytes, hydroxylation of the methyl group on the oxadiazole ring and double-bond isomerization were the most abundant metabolites observed. No major species differences were found in terms of microsomal metabolite profiles. The use of LC with UV and MS detection is highlighted, as well as information from tandem mass spectrometry and NMR.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Hepatocitos/metabolismo , Microsomas Hepáticos/metabolismo , Quinolinas/farmacocinética , Animales , Cromatografía Liquida/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Perros , Humanos , Macaca mulatta , Espectrometría de Masas/métodos , Ratones , Ratas , Saimiri , Especificidad de la Especie , Espectrofotometría Ultravioleta/métodosRESUMEN
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Glicoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Adenosina Desaminasa/metabolismo , Administración Oral , Amidas/química , Animales , Disponibilidad Biológica , Dipeptidil Peptidasa 4/metabolismo , Perros , Glicoproteínas/metabolismo , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Estructura Molecular , Nitrógeno/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Piridonas/química , Piridonas/farmacocinética , Ratas , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Broncoconstricción/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cobayas , Humanos , Concentración 50 Inhibidora , Inhibidores de Fosfodiesterasa/toxicidad , Quinolinas/toxicidad , Ratas , Saimiri , Ovinos , Relación Estructura-Actividad , Vómitos/inducido químicamenteRESUMEN
anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.
Asunto(s)
Dipeptidil Peptidasa 4/química , Fenilalanina/síntesis química , Fenilalanina/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Administración Oral , Animales , Glucemia/metabolismo , Proteínas de Unión al ADN/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Ratones , Estructura Molecular , Fenilalanina/farmacocinética , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Especificidad por Sustrato , Transactivadores/metabolismo , Regulador Transcripcional ERGRESUMEN
In-house screening of the Merck sample collection identified proline derived homophenylalanine 3 as a DPP-IV inhibitor with modest potency (DPP-IV IC50=1.9 microM). Optimization of 3 led to compound 37, which is among the most potent and selective DPP-IV inhibitors discovered to date.