1027211-26-2Relevant articles and documents
Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer
Wang, Lei,Jiang, Jingsheng,Zhang, Lixiao,Zhang, Qiuyue,Zhou, Jianrui,Li, Li,Xu, Xiaoli,You, Qidong
, p. 1281 - 1297 (2020)
Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-Activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 μM) and cellular inhibitory activity (IC50 = 1.73 μM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.
Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core
Zhang, Qiuyue,Wu, Xuexuan,Zhou, Jianrui,Zhang, Lixiao,Xu, Xiaoli,Zhang, Lianshan,You, Qidong,Wang, Lei
, (2020/11/02)
HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (KD = 5.52 μM) and antiproliferative activity (IC50 = 6.34 μM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.
N - (4 - (pyrimidine -4 - amino) phenyl) sulfonamide inhibitors or pharmaceutically acceptable salts thereof, its preparation and use (by machine translation)
-
Paragraph 0066; 0068, (2019/06/05)
The invention discloses N - (4 - (pyrimidine - 4 - amino) phenyl) sulfonamide inhibitors or pharmaceutically acceptable salts thereof, also disclosed the above-mentioned inhibitors or pharmaceutically acceptable salts thereof of the preparation method and use thereof. The compounds of this invention can be in the cell and animal level inhibiting Hsp90 - Cdc37 interaction client protein expression, used for the treatment or prevention by the Hsp90 mediated signal path of various diseases, such as colon cancer, liver cancer, breast cancer, prostate cancer and pancreatic cancer and other various types of cancer. (by machine translation)
METHODS FOR INHIBITING NECROPTOSIS
-
, (2015/12/30)
The present invention relates to methods for inhibiting necroptosis; screening methods for identifying compounds which inhibit necroptosis; and compounds for the inhibition of necroptosis, which may be useful in the treatment of conditions associated with deregulated necroptosis.
NOVEL COMPOUNDS
-
Page/Page column 29-30, (2008/12/05)
The present invention relates to pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such pyrimidine derivatives are potentially useful
