RESUMO
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/química , Citocinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
Assuntos
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inibidores , Pirróis/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Pirróis/síntese química , Pirróis/farmacocinética , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transplante HeterólogoRESUMO
A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.
RESUMO
G9a is a histone lysine methyltransferase responsible for the methylation of histone H3 lysine 9. The discovery of A-366 arose from a unique diversity screening hit, which was optimized by incorporation of a propyl-pyrrolidine subunit to occupy the enzyme lysine channel. A-366 is a potent inhibitor of G9a (IC50: 3.3 nM) with greater than 1000-fold selectivity over 21 other methyltransferases.
RESUMO
Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinases , Linhagem Celular , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células 3T3 , Animais , Azepinas/química , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.