title: Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.
abstract: A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.
authors.affiliation: Biotica Technology Limited, Chesterford Research Park, Nr. Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zhang
authors.forename: Sabine
authors.initials: S
authors.lastname: Gaisser
authors.forename: Mohammad
authors.initials: M
authors.lastname: Nur-E-Alam
authors.forename: Lesley S
authors.initials: LS
authors.lastname: Sheehan
authors.forename: William A
authors.initials: WA
authors.lastname: Vousden
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Gaitatzis
authors.forename: Gerrard
authors.initials: G
authors.lastname: Peck
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Coates
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Markus
authors.initials: M
authors.lastname: Radzom
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Foster
authors.forename: Rose M
authors.initials: RM
authors.lastname: Sheridan
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Gregory
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence
authors.initials: L
authors.lastname: Pearl
authors.forename: Susan M
authors.initials: SM
authors.lastname: Boyd
authors.forename: Barrie
authors.initials: B
authors.lastname: Wilkinson
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Martin
mesh_terms: D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005818:Genetic Engineering; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure
chemical_list: D016227:Benzoquinones; D001688:Biological Products; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C025514:macbecin I