title: Structure-based design and synthesis of (5-arylamino-2H-pyrazol-3-yl)-biphenyl-2',4'-diols as novel and potent human CHK1 inhibitors.
abstract: 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.
authors: 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
authors: Min
authors: M
authors: Teng
authors: Jinjiang
authors: J
authors: Zhu
authors: Michael D
authors: MD
authors: Johnson
authors: Ping
authors: P
authors: Chen
authors: Jill
authors: J
authors: Kornmann
authors: Enhong
authors: E
authors: Chen
authors: Alessandra
authors: A
authors: Blasina
authors: James
authors: J
authors: Register
authors: Kenna
authors: K
authors: Anderes
authors: Caroline
authors: C
authors: Rogers
authors: Yali
authors: Y
authors: Deng
authors: Sacha
authors: S
authors: Ninkovic
authors: Stephan
authors: S
authors: Grant
authors: Qiyue
authors: Q
authors: Hu
authors: Karen
authors: K
authors: Lundgren
authors: Zhengwei
authors: Z
authors: Peng
authors: Robert S
authors: RS
authors: Kania
mesh_terms: 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
chemical_list: 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