Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
Huth
Jeffrey R
JR
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Park
Chang
C
Petros
Andrew M
AM
Kunzer
Aaron R
AR
Wendt
Michael D
MD
Wang
Xilu
X
Lynch
Christopher L
CL
Mack
Jamey C
JC
Swift
Kerry M
KM
Judge
Russell A
RA
Chen
Jun
J
Richardson
Paul L
PL
Jin
Sha
S
Tahir
Stephen K
SK
Matayoshi
Edward D
ED
Dorwin
Sarah A
SA
Ladror
Uri S
US
Severin
Jean M
JM
Walter
Karl A
KA
Bartley
Diane M
DM
Fesik
Stephen W
SW
Elmore
Steven W
SW
Hajduk
Philip J
PJ
D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D010446:Peptide Fragments