Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
Takeda California, 10410 Science Center Drive, San Diego 92121, USA. Electronic address: andre.kiryanov@takeda.com.
Andre
A
Kiryanov
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Srinivasa
S
Natala
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Benjamin
B
Jones
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Christopher
C
McBride
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Victoria
V
Feher
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Betty
B
Lam
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Yan
Y
Liu
Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan.
Kouhei
K
Honda
Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan.
Noriko
N
Uchiyama
Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan.
Tomohiro
T
Kawamoto
Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan.
Yuichi
Y
Hikichi
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Lilly
L
Zhang
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
David
D
Hosfield
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Robert
R
Skene
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Hua
H
Zou
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Jeffrey
J
Stafford
Takeda California, 10410 Science Center Drive, San Diego 92121, USA.
Xiaodong
X
Cao
Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-855, Japan.
Takashi
T
Ichikawa
D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C117197:imidazolone
Antitumor activity; Multidrug resistance; PLK1 inhibitor; Structure-based drug design