RESUMEN
Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.
Asunto(s)
Receptores de Factores de Crecimiento Transformadores beta , Animales , Ratones , SolventesRESUMEN
Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.
Asunto(s)
Amidas/química , Diseño de Fármacos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Amidas/toxicidad , Animales , Sitios de Unión , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Células RAW 264.7 , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Relación Estructura-ActividadRESUMEN
The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismoRESUMEN
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356µM and AR binding IC50=<0.03µM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.
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Antagonistas de Andrógenos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/efectos de los fármacos , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacocinética , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Proteínas HSP90 de Choque Térmico/metabolismo , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Masculino , Ratones , Modelos MolecularesRESUMEN
Total syntheses of two new (+/-)-kempane derivatives 30 and 47 were achieved with transannular Diels-Alder reaction (TADA) serving as the key step for the stereoselective formation of tricyclic [6.6.5] system 3. This synthetic approach also reveals that the geometry of the C3 group of such a tricyclic system plays an important role for the formation of the seven-membered kempane skeleton.
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Diterpenos/síntesis química , Compuestos Macrocíclicos/síntesis química , Animales , Ciclización , Diterpenos/química , Diterpenos/aislamiento & purificación , Isópteros/química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/aislamiento & purificación , Estructura MolecularRESUMEN
Stereoselective synthesis of the potentially biologically valuable 5beta-lanosteroidal-type backbone was achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40 and their cycloaddition with chiral cyclohexenone 25 and further functional group manipulations resulted in highly functionalized tetracyclic intermediates 28 and 44. These synthetic intermediates could lead to the total synthesis of new lanosterol-based inhibitors.