2QG2

HSP90 complexed with A917985

Summary for 2QG2

• Entry DOI: 10.2210/pdb2qg2/pdb
• Related: 2QF6 2QFO 2QG0
• Descriptor: Heat shock protein HSP 90-alpha, 3-({2-[(2-AMINO-6-METHYLPYRIMIDIN-4-YL)ETHYNYL]BENZYL}AMINO)-1,3-OXAZOL-2(3H)-ONE (3 entities in total)
• Functional Keywords: protein-inhibitor complex, chaperone
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 23469.58

Authors

Park, C.H. (deposition date: 2007-06-28, release date: 2008-07-01, Last modification date: 2023-08-30)

Primary citation

Huth, J.R.,Park, C.,Petros, A.M.,Kunzer, A.R.,Wendt, M.D.,Wang, X.,Lynch, C.L.,Mack, J.C.,Swift, K.M.,Judge, R.A.,Chen, J.,Richardson, P.L.,Jin, S.,Tahir, S.K.,Matayoshi, E.D.,Dorwin, S.A.,Ladror, U.S.,Severin, J.M.,Walter, K.A.,Bartley, D.M.,Fesik, S.W.,Elmore, S.W.,Hajduk, P.J.
Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
Chem.Biol.Drug Des., 70:1-12, 2007

PubMed Abstract: The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.

PubMed: 17630989
DOI: 10.1111/j.1747-0285.2007.00535.x

Experimental method

X-RAY DIFFRACTION (1.8 Å)