Your browser doesn't support javascript.
loading
Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.
Saidahmatov, Abdusaid; Li, Jianan; Xu, Shihao; Hu, Xiaobei; Gao, Xiangqian; Kan, Weijuan; Gao, Lixin; Li, Cong; Shi, Yuqiang; Sheng, Li; Wang, Peipei; Zhou, Yubo; Liang, Xuewu; Li, Jia; Liu, Hong.
Afiliação
  • Saidahmatov A; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Li J; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Xu S; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • Hu X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Gao X; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Kan W; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Gao L; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China.
  • Li C; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • Shi Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Sheng L; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Wang P; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Zhou Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Liang X; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Li J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • Liu H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
J Med Chem ; 67(17): 15220-15245, 2024 Sep 12.
Article em En | MEDLINE | ID: mdl-39178382
ABSTRACT
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
Assuntos
Aminopiridinas; Antineoplásicos; Inibidores de Histona Desacetilases; Pirimidinas; Humanos; Animais; Inibidores de Histona Desacetilases/farmacologia; Inibidores de Histona Desacetilases/química; Inibidores de Histona Desacetilases/síntese química; Inibidores de Histona Desacetilases/uso terapêutico; Antineoplásicos/farmacologia; Antineoplásicos/química; Antineoplásicos/síntese química; Antineoplásicos/uso terapêutico; Linhagem Celular Tumoral; Aminopiridinas/farmacologia; Aminopiridinas/síntese química; Aminopiridinas/química; Pirimidinas/farmacologia; Pirimidinas/química; Pirimidinas/síntese química; Pirimidinas/uso terapêutico; Relação Estrutura-Atividade; Camundongos; Apoptose/efeitos dos fármacos; Proliferação de Células/efeitos dos fármacos; Inibidores de Proteínas Quinases/farmacologia; Inibidores de Proteínas Quinases/química; Inibidores de Proteínas Quinases/síntese química; Inibidores de Proteínas Quinases/uso terapêutico; Neoplasias Hematológicas/tratamento farmacológico; Neoplasias Hematológicas/patologia; Quinase 9 Dependente de Ciclina/antagonistas & inibidores; Quinase 9 Dependente de Ciclina/metabolismo; Ensaios Antitumorais Modelo de Xenoenxerto; Histona Desacetilase 1/antagonistas & inibidores; Histona Desacetilase 1/metabolismo; Descoberta de Drogas; Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores; Tirosina Quinase 3 Semelhante a fms/metabolismo; Neoplasias/tratamento farmacológico; Neoplasias/patologia; Camundongos Endogâmicos BALB C; Ensaios de Seleção de Medicamentos Antitumorais; Camundongos Nus

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Inibidores de Histona Desacetilases / Aminopiridinas / Antineoplásicos Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Inibidores de Histona Desacetilases / Aminopiridinas / Antineoplásicos Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China