Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.
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.
Zhang
Ming-Qiang
MQ
Biotica Technology Limited, Chesterford Research Park, Nr. Saffron Walden, Essex CB10 1XL, United Kingdom.
Gaisser
Sabine
S
Nur-E-Alam
Mohammad
M
Sheehan
Lesley S
LS
Vousden
William A
WA
Gaitatzis
Nikolaos
N
Peck
Gerrard
G
Coates
Nigel J
NJ
Moss
Steven J
SJ
Radzom
Markus
M
Foster
Teresa A
TA
Sheridan
Rose M
RM
Gregory
Matthew A
MA
Roe
S Mark
SM
Prodromou
Chrisostomos
C
Pearl
Laurence
L
Boyd
Susan M
SM
Wilkinson
Barrie
B
Martin
Christine J
CJ
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
D016227:Benzoquinones; D001688:Biological Products; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C025514:macbecin I