2XHX

Structure of HSP90 with small molecule inhibitor bound

Summary for 2XHX

• Entry DOI: 10.2210/pdb2xhx/pdb
• Related: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYI 1UYK 1UYL 1YC1 1YC3 1YC4 1YER 1YES 1YET 2BSM 2BT0 2BUG 2BYH 2BYI 2BZ5 2C2L 2CCS 2CCT 2CCU 2CDD 2FWY 2FWZ 2JJC 2UWD 2VCI 2VCJ 2WI1 2WI2 2WI3 2WI4 2WI5 2WI6 2WI7 2XAB 2XDK 2XDL 2XDS 2XDU 2XDX 2XHR 2XHT
• Descriptor: HEAT SHOCK PROTEIN HSP 90-ALPHA, 2-TERT-BUTYL-4-(1,3-DIHYDRO-2H-ISOINDOL-2-YLCARBONYL)PHENOL (3 entities in total)
• Functional Keywords: hsp90, chaperone, atp binding domain, n-terminal domain, stress response
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 28268.74

Authors

Murray, C.W.,Carr, M.G.,Callaghan, O.,Chessari, G.,Congreve, M.,Cowan, S.,Coyle, J.E.,Downham, R.,Figueroa, E.,Frederickson, M.,Graham, B.,McMenamin, R.,OBrien, M.A.,Patel, S.,Phillips, T.R.,Williams, G.,Woodhead, A.J.,Woolford, A.J.A. (deposition date: 2010-06-21, release date: 2010-09-01, Last modification date: 2024-05-08)

Primary citation

Murray, C.W.,Carr, M.G.,Callaghan, O.,Chessari, G.,Congreve, M.,Cowan, S.,Coyle, J.E.,Downham, R.,Figueroa, E.,Frederickson, M.,Graham, B.,Mcmenamin, R.,O'Brien, M.A.,Patel, S.,Phillips, T.R.,Williams, G.,Woodhead, A.J.,Woolford, A.J.A.
Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency.
J.Med.Chem., 53:5942-, 2010

PubMed Abstract: Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.

PubMed: 20718493
DOI: 10.1021/JM100059D

Experimental method

X-RAY DIFFRACTION (2.801 Å)