RESUMEN
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.
Asunto(s)
Antineoplásicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Perros , Relación Estructura-Actividad , Femenino , Descubrimiento de Drogas , Taxoides/farmacología , Taxoides/farmacocinética , Taxoides/uso terapéutico , Taxoides/química , Docetaxel/farmacología , Docetaxel/uso terapéutico , Docetaxel/farmacocinética , Docetaxel/químicaRESUMEN
This letter describes a focused exercise to explore the role of the ß-amino carboxamide moiety found in all of the first generation M4 PAMs and question if the NH2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the ß-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH2, generating des-amino congeners and surveyed other functional groups in the ß-position. These modifications led to weak M4 PAMs with poor DMPK properties. Cyclization of the ß-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M4 PAMs, many as potent as the classical bicyclic ß-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the ß-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M4 PAM activity within classical bicyclic M4 PAM scaffolds.
Asunto(s)
Amidas/farmacología , Receptor Muscarínico M4/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Enlace de Hidrógeno , Ligandos , Estructura Molecular , Receptor Muscarínico M4/metabolismo , Relación Estructura-ActividadRESUMEN
Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in â¼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas/normas , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína SOS1/agonistas , Proteína SOS1/metabolismo , Bencimidazoles/química , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factores de Intercambio de Guanina Nucleótido/química , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Fosforilación , Conformación Proteica , Proteínas Proto-Oncogénicas p21(ras)/química , Relación Estructura-ActividadRESUMEN
WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.
Asunto(s)
Diseño de Fármacos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/química , Imidazoles/química , Imidazoles/farmacología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Relación Estructura-ActividadRESUMEN
This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Asunto(s)
Descubrimiento de Drogas , Morfolinas/farmacología , Pirazoles/farmacología , Receptor Muscarínico M1/agonistas , Animales , Células CHO , Cricetulus , Humanos , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-ActividadRESUMEN
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
Asunto(s)
Ácidos Picolínicos/farmacología , Pirroles/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Sulfonamidas/farmacología , Regulación Alostérica , Animales , Microsomas Hepáticos/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Triazoles/farmacologíaRESUMEN
The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.
Asunto(s)
Fármacos actuantes sobre Aminoácidos Excitadores/síntesis química , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Ácidos Picolínicos/farmacología , Pirazoles/síntesis química , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica/efectos de los fármacos , Amidas/química , Amidas/farmacología , Animales , Cromatografía Líquida de Alta Presión , Fármacos actuantes sobre Aminoácidos Excitadores/química , Humanos , Ácidos Picolínicos/química , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Relación Estructura-ActividadRESUMEN
Herein we describe the discovery and development of a novel class of M(4) positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC(50)=1.3 µM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1h, [Brain]=10.3 µM, B:P=0.85).
Asunto(s)
Encéfalo/metabolismo , Niacinamida/análogos & derivados , Receptor Muscarínico M4/química , Regulación Alostérica , Amidas/química , Animales , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Niacinamida/química , Niacinamida/farmacocinética , Ratas , Receptor Muscarínico M4/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we report the discovery and SAR of a novel antagonist of metabotropic glutamate receptor 4 (mGlu(4)). The antagonist was discovered via a molecular switch from a closely related mGlu(4) positive allosteric modulator (PAM). This antagonist (VU0448383) displays an IC(50) value of 8.2±0.4 µM and inhibits an EC(80) glutamate response by 63.1±6.6%.
Asunto(s)
Diseño de Fármacos , Piridinas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Regulación Alostérica , Animales , Células Cultivadas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca(2+) rise in response to stimulation of mouse TRPC4ß by µ-opioid receptors. ML204 inhibited TRPC4ß-mediated intracellular Ca(2+) rise with an IC(50) value of 0.96 µm and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4ß currents activated through either µ-opioid receptor stimulation or intracellular dialysis of guanosine 5'-3-O-(thio)triphosphate (GTPγS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 µm ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPγS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.
Asunto(s)
Indoles/farmacología , Piperidinas/farmacología , Canales Catiónicos TRPC/antagonistas & inhibidores , Animales , Cationes/metabolismo , Femenino , Colorantes Fluorescentes/metabolismo , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Indoles/química , Intestinos/citología , Activación del Canal Iónico/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Piperidinas/química , Receptores Muscarínicos/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , Canales Catiónicos TRPC/metabolismoRESUMEN
Herein we report a general synthesis of 1,3-diarylsubstituted indazoles utilizing a two-step Suzuki cross-coupling/deprotection/N-arylation sequence. This procedure proceeds in excellent overall yield starting from the 3-iodo-N-Boc indazole derivative allowing for rapid access to these compounds.
RESUMEN
The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/química , Administración Oral , Compuestos de Anilina/química , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Piridinas/síntesis química , Piridinas/farmacología , Receptor de Insulina/metabolismoRESUMEN
The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.