RESUMO
The synthesis and structure-activity relationships (SAR) of Chk1 inhibitors based on a 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one core are described. Specifically, an exploration of the 7 and 8 positions on this previously disclosed core afforded compounds with improved enzymatic and cellular potency.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Quinases/metabolismo , Antineoplásicos/síntese química , Benzodiazepinonas/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Inibidores Enzimáticos/síntese química , Células HeLa , Humanos , Modelos Químicos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure-activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with K(i) values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Modelos Moleculares , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Isoxazóis/química , Conformação Molecular , Estrutura Molecular , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.
Assuntos
Antineoplásicos/síntese química , Azepinas/síntese química , Benzodiazepinonas/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Benzodiazepinonas/química , Benzodiazepinonas/farmacologia , Disponibilidade Biológica , Camptotecina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Doxorrubicina/farmacologia , Desenho de Fármacos , Sinergismo Farmacológico , Humanos , Camundongos , Modelos Moleculares , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC(50)=3.31, 3.08, and 3.13microM) and enhanced doxorubicin cytotoxicity (IC(50)=0.54, 1.27, and 0.96microM) while displaying no single agent activity, respectively.
Assuntos
Compostos Macrocíclicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Ureia/síntese química , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Células HeLa , Humanos , Compostos Macrocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3ß, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.
RESUMO
Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Oxidiazóis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Piridinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Piridinas/farmacocinética , Piridinas/farmacologia , Relação Estrutura-Atividade , Temozolomida , Transplante HeterólogoRESUMO
A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.