Structure-based design and synthesis of (5-arylamino-2H-pyrazol-3-yl)-biphenyl-2',4'-diols as novel and potent human CHK1 inhibitors.
The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
Teng
Min
M
Department of Medicinal Chemistry, Pfizer Global Research and Development, La Jolla, Inc., 10770 Science Center Drive, San Diego, California 92121-1194, USA. min.teng@biogenidec.com
Zhu
Jinjiang
J
Johnson
Michael D
MD
Chen
Ping
P
Kornmann
Jill
J
Chen
Enhong
E
Blasina
Alessandra
A
Register
James
J
Anderes
Kenna
K
Rogers
Caroline
C
Deng
Yali
Y
Ninkovic
Sacha
S
Grant
Stephan
S
Hu
Qiyue
Q
Lundgren
Karen
K
Peng
Zhengwei
Z
Kania
Robert S
RS
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011471:Prostatic Neoplasms; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine