RESUMO
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.
Assuntos
Receptores de Fatores de Crescimento Transformadores beta , Animais , Camundongos , SolventesRESUMO
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.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química , Pirimidinas/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismoRESUMO
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.
Assuntos
Amidas/química , Desenho de Fármacos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Amidas/toxicidade , Animais , Sítios de Ligação , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Células RAW 264.7 , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas de Androgênios/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacocinética , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Masculino , Camundongos , Modelos MolecularesRESUMO
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.
Assuntos
Diterpenos/síntese química , Compostos Macrocíclicos/síntese química , Animais , Ciclização , Diterpenos/química , Diterpenos/isolamento & purificação , Isópteros/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/isolamento & purificação , Estrutura MolecularRESUMO
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.