RESUMEN
Trifluoromethyl N,N-aminals are important precursors allowing access to fluorinated building blocks. In this work, the direct synthesis of trifluoromethyl N,N-aminals from nitrogen containing heterocycles is reported using argon plasma in a continuous flow microreactor without any additives or metal catalysts. Their transformation to N-trifluoroethyl amines is also reported.
RESUMEN
Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Corazón/efectos de los fármacos , Hidroxicloroquina/química , Hidroxicloroquina/farmacología , Canales Iónicos/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Arritmias Cardíacas/inducido químicamente , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Canales de Potasio Éter-A-Go-Go , Humanos , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Ramos Subendocárdicos/efectos de los fármacos , Conejos , EstereoisomerismoRESUMEN
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Receptores de Estrógenos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , RatonesRESUMEN
More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Animales , Neoplasias de la Mama/metabolismo , Cristalografía por Rayos X , Perros , Resistencia a Antineoplásicos , Femenino , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Modelos Moleculares , Ratas , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Laurent Schio speaks to Benjamin Walden, Commissioning Editor. Laurent Schio is leading the group of Integrated Drug Discovery of Sanofi, France. He joined Sanofi more than 25 years ago and is an organic chemist by training. He has made most of his career in medicinal chemistry supporting and leading projects, especially in the anti-infective and then in the oncology fields. He has developed a strong expertise in kinases and lately has contributed to the discovery of several clinical candidates for cancer treatment.
Asunto(s)
Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Descubrimiento de Drogas/tendencias , Química Farmacéutica , Industria Farmacéutica , Humanos , Simulación de Dinámica MolecularRESUMEN
The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.
Asunto(s)
Benzotiazoles/farmacología , Benzotiazoles/farmacocinética , Descubrimiento de Drogas , Neoplasias Experimentales/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Benzotiazoles/administración & dosificación , Benzotiazoles/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Relación Estructura-Actividad , Urea/administración & dosificación , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, ß, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the ß subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the ß-isoform do not interact directly with either PI3Kß or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.
Asunto(s)
Fosfatidilinositol 3-Quinasas/metabolismo , Subunidades de Proteína/metabolismo , Solventes/química , Agua/química , Ligandos , Simulación de Dinámica Molecular , Fosfatidilinositol 3-Quinasas/química , Conformación Proteica , Subunidades de Proteína/química , Especificidad por Sustrato , TermodinámicaRESUMEN
A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.
Asunto(s)
Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Aminoquinolinas/química , Línea Celular Tumoral , AMP Cíclico/biosíntesis , Humanos , Modelos Moleculares , Inhibidores de Fosfodiesterasa 4/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Pirimidinonas/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Células CACO-2 , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas Clase III/química , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Masculino , Ratones SCID , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Neoplasias/patología , Unión Proteica , Estructura Terciaria de Proteína , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratas Sprague-Dawley , Homología de Secuencia de Aminoácido , Termodinámica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasas/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinolonas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/química , Aurora Quinasa A/metabolismo , Aurora Quinasa B/antagonistas & inhibidores , Aurora Quinasa B/química , Aurora Quinasa B/metabolismo , Aurora Quinasa C/antagonistas & inhibidores , Aurora Quinasa C/química , Aurora Quinasa C/metabolismo , Aurora Quinasas/química , Aurora Quinasas/metabolismo , Bencimidazoles/química , Bencimidazoles/metabolismo , Femenino , Células HCT116 , Humanos , Ratones SCID , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Quinolonas/química , Quinolonas/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration-approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.
Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Pirimidinonas/farmacología , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Antineoplásicos/síntesis química , Autofagia/genética , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasas Clase III/química , Fosfatidilinositol 3-Quinasas Clase III/genética , Sinergismo Farmacológico , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Everolimus , Expresión Génica , Humanos , Riñón/enzimología , Riñón/patología , Cinética , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/síntesis química , Pirimidinonas/síntesis química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Transducción de Señal , Sirolimus/síntesis química , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.
Asunto(s)
Antineoplásicos/farmacología , Crisis Blástica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Factor de Transcripción STAT5/metabolismo , Antineoplásicos/química , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Crisis Blástica/metabolismo , Crisis Blástica/patología , Femenino , Células HL-60 , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Factor de Transcripción STAT5/genéticaRESUMEN
Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes in the presence or absence of JAK2 blockade. One of the top hits identified was MYC, an oncogenic transcription factor that is difficult to inhibit directly, but could be targeted by modulation of upstream regulatory elements such as kinases. We demonstrate herein that PIM kinase inhibitors efficiently suppress MYC protein levels in MPN cell lines. Importantly, overexpression of MYC restores the viability of PIM inhibitor-treated cells, revealing causal relationship between MYC down-regulation and cell growth inhibition by PIM compounds. Combination of various PIM inhibitors with a JAK2 inhibitor results in significant synergistic growth inhibition of multiple MPN cancer cell lines and induction of apoptosis. Mechanistic studies revealed strong downregulation of phosphorylated forms of S6 and 4EBP1 by JAK2/PIM inhibitor combination treatment. Finally, such combination was effective in eradicating in vitro JAK2 inhibitor-resistant MPN clones, where MYC is consistently up-regulated. These findings demonstrate that simultaneous suppression of JAK2 and PIM kinase activity by small molecule inhibitors is more effective than either agent alone in suppressing MPN cell growth. Our data suggest that JAK2 and PIM combination might warrant further investigation for the treatment of JAK2-driven hematologic malignancies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Trastornos Mieloproliferativos/enzimología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Immunoblotting , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kß has been identified. This Letter reports the optimization of this compound class to develop PI3Kß isoform-selective inhibitors with suitable pharmacological properties.
Asunto(s)
Amidas/química , Ácidos Carboxílicos/química , Indoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Amidas/síntesis química , Animales , Sitios de Unión , Células CACO-2 , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Humanos , Masculino , Simulación del Acoplamiento Molecular , Permeabilidad/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Tiazoles/químicaRESUMEN
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.
Asunto(s)
Antineoplásicos/química , Indoles/química , Neoplasias/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinonas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Humanos , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Microsomas Hepáticos/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular , Trasplante de Neoplasias , Neoplasias/enzimología , Fosfohidrolasa PTEN/genética , Unión Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Ratas Desnudas , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The phosphine-promoted [3 + 2] cyclizations between γ-substituted allenoates and arylideneoxindoles have been applied to the stereoselective synthesis of spiro(cyclopentene)oxindoles with trisubstituted cyclopentene units. It has been demonstrated that PPh(3) operates a very efficient control of the relative stereochemistry of the three stereogenic centers of the final spiranic products. Focused experiments have been carried out then so as to access carbocyclic analogues of an important series of anticancer agents inhibiting MDM2-p53 interactions.
Asunto(s)
Ciclopentanos/química , Ciclopentanos/síntesis química , Indoles/química , Indoles/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Alcadienos/química , Catálisis , Ciclización , Estructura Molecular , FosfinasRESUMEN
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Pirimidinonas/química , Pirimidinonas/farmacología , Anilidas/química , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Cristalografía por Rayos X , Femenino , Eliminación de Gen , Humanos , Masculino , Ratones , Ratones SCID , Modelos Moleculares , Fosfohidrolasa PTEN/genética , Próstata/citología , Próstata/efectos de los fármacos , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Pirimidinonas/farmacocinética , Relación Estructura-ActividadRESUMEN
Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kß has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kß-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kß and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kß isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Benzoxazoles/síntesis química , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Pirimidinonas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Humanos , Isoenzimas/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/patología , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N-Heterocyclic carbene (NHC) platinum complexes have been highlighted as a promising and original platform for building new cytotoxic drugs of the cisplatin series. Mixed NHC-amine Pt(II) complexes have been prepared via a facile and modular two step sequence leading to trans-configured square planar species. They have been characterized by spectroscopic methods and X-ray diffraction studies. Their efficiency against both cisplatin sensitive (CEM and H460) and resistant (A2780/DDP, CH1/DDP, and SK-OV-3) cell lines has been demonstrated by in vitro experiments.