2XX4

Macrolactone Inhibitor bound to HSP90 N-term

Summary for 2XX4

• Entry DOI: 10.2210/pdb2xx4/pdb
• Related: 1A4H 1AH6 1AH8 1AM1 1AMW 1BGQ 1HK7 1US7 1USU 1USV 1ZW9 1ZWH 2AKP 2BRC 2BRE 2CG9 2CGE 2CGF 2IWS 2IWU 2IWX 2VW5 2VWC 2WEP 2WEQ 2WER 2XD6 2XX2 2XX5 2YGA 2YGE 2YGF
• Descriptor: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, (E)-ETHYL 13-CHLORO-14,16-DIHYDROXY-1,11-DIOXO-1,2,3,4,7,8,9,10,11,12-DECAHYDROBENZO[C][1]AZACYCLOTETRADECINE-10-CARBOXYLATE (3 entities in total)
• Functional Keywords: chaperone
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Cellular location: Cytoplasm : P02829
• Total number of polymer chains: 1
• Total formula weight: 24620.46

Authors

Moody, C.J.,Prodromou, C.,Pearl, L.H.,Roe, S.M. (deposition date: 2010-11-08, release date: 2011-11-16, Last modification date: 2023-12-20)

Primary citation

Day, J.E.,Sharp, S.Y.,Rowlands, M.G.,Aherne, W.,Hayes, A.,Raynaud, F.I.,Lewis, W.,Roe, S.M.,Prodromou, C.,Pearl, L.H.,Workman, P.,Moody, C.J.
Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies.
Acs Chem.Biol., 6:1339-, 2011

PubMed Abstract: A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have been prepared by chemical synthesis and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves, as key steps, ring opening of an isocoumarin intermediate, followed by a ring-closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 confirms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N-benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological profile equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.

PubMed: 21932796
DOI: 10.1021/CB200196E

Experimental method

X-RAY DIFFRACTION (2.199 Å)