912544-63-9Relevant academic research and scientific papers
Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency
Murray, Christopher W.,Carr, Maria G.,Callaghan, Owen,Chessari, Gianni,Congreve, Miles,Cowan, Suzanna,Coyle, Joseph E.,Downham, Robert,Figueroa, Eva,Frederickson, Martyn,Graham, Brent,McMenamin, Rachel,O'Brien, M. Alistair,Patel, Sahil,Phillips, Theresa R.,Williams, Glyn,Woodhead, Andrew J.,Woolford, Alison J.-A.
supporting information; experimental part, p. 5942 - 5955 (2010/11/04)
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 1000000-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.
PHARMACEUTICAL COMPOUNDS
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Page/Page column 97, (2008/06/13)
The invention provides a compound for use as an inhibitor of Hsp90, the compound having the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; C 1-5 hydrocarbyl and C 1-5 hydrocarbyloxy; wherein the C 1-5 hydrocarbyl and C 1-5 hydrocarbyloxy moieties are each optionally substituted by one or more substituents selected from hydroxy, halogen, C 1-2 alkoxy, amino, mono- and di-C 1-2 alkylamino, and aryl and heteroaryl groups of 5 to 12 ring members; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and mono- or di-C 1-5 hydrocarbyl-amino, wherein the acyclic Ci-5 hydrocarbyl group and the mono and di-C 1-5 hydrocarbylamino moieties in each instance are optionally substituted by one or more substituents selected from hydroxy, halogen, C 1-2 alkoxy, amino, mono- and di-C 1-2 alkylamino, and aryl and heteroaryl groups of 5 to 12 ring members; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and R5 and R6 are as defined in the claims.
