Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors

TY - JOUR

T1 - Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors

AU - Akue-Gedu, Rufine

AU - Rossignol, Emilie

AU - Azzaro, Stephane

AU - Knapp, Stefan

AU - Filippakopoulos, Panagis

AU - Bullock, Alex N.

AU - Bain, Jenny

AU - Cohen, Philip

AU - Prudhomme, Michelle

AU - Anizon, Fabrice

AU - Moreau, Pascale

PY - 2009/10/22

Y1 - 2009/10/22

N2 - Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3-a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC50 values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases.

AB - Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3-a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC50 values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases.

KW - HUMAN PANCREATIC-CANCER

KW - BAD-MEDIATED APOPTOSIS

KW - BINDING MODE

KW - STRUCTURAL BASIS

KW - PROTEIN

KW - PROTOONCOGENE

KW - PHOSPHORYLATES

KW - SPECIFICITY

KW - CELLS

KW - TRANSCRIPTION

U2 - 10.1021/jm901018f

DO - 10.1021/jm901018f

M3 - Article

SN - 0022-2623

VL - 52

SP - 6369

EP - 6381

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -