RESUMO
A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization.
Assuntos
Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Neoplasias/tratamento farmacológicoRESUMO
Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Quinolinas/química , Caseína Quinase II/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Proteica , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Naftiridinas/química , Naftiridinas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Triazóis/química , Triazóis/farmacologiaRESUMO
Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Pirróis/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células Cultivadas , AMP Cíclico/biossíntese , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Hipófise/citologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismo , Relação Estrutura-AtividadeRESUMO
SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.