7C04
Crystal structure of human Trap1 with DN203492
Summary for 7C04
| Entry DOI | 10.2210/pdb7c04/pdb |
| Descriptor | Heat shock protein 75 kDa, mitochondrial, 4-chloranyl-1-[[2-methoxy-4-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-6-amine (3 entities in total) |
| Functional Keywords | trap1, selectivity, mitochondria, hsp90, anticancer, drug, chaperone |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 26137.58 |
| Authors | |
| Primary citation | Kim, D.,Kim, S.Y.,Kim, D.,Yoon, N.G.,Yun, J.,Hong, K.B.,Lee, C.,Lee, J.H.,Kang, B.H.,Kang, S. Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models. Bioorg.Chem., 101:103901-103901, 2020 Cited by PubMed Abstract: TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth. PubMed: 32590225DOI: 10.1016/j.bioorg.2020.103901 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
Download full validation report
