Novel compounds with antiproliferative activity against imatinib-resistant cell lines.
Chronic myelogenous leukemia is caused by the Bcr-Abl hybrid gene that encodes the p210Bcr-Abl chimeric oncoprotein. Although it reduces the total body burden of leukemia cells, the use of imatinib mesylate as a single agent may be accompanied by the evolution of resistance due mainly to the acquisition of point mutations. Imatinib has been combined with drugs that inhibit both the active and the inactive states of the p210Bcr-Abl kinase. These combinations have reduced but not completely eliminated the rate at which point mutations are acquired in the p210Bcr-Abl kinase. Thus, it is important to identify additional new inhibitors of the p210Bcr-Abl kinase. One possible method to prevent evolution of resistance is to simultaneously use multiple kinase inhibitors each with a different mechanism of action. To identify such a new class of inhibitors that could suppress the growth of chronic myelogenous leukemia cells and prevent the evolution of cells that are resistant to imatinib, we screened two low-complexity libraries of compounds based on planar and linear scaffolds. These libraries were screened using a cell-based assay for molecules that suppress p210Bcr-Abl-dependent cell growth. The application of this method resulted in the isolation of two new classes of drugs, both of which inhibited imatinib-resistant cells in the low micromolar range. Some of these drugs were potent inhibitors not only of Abl tyrosine kinase but also of the Src, Lyn, and Fyn tyrosine kinases.
Lerma
Enrica I
EI
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA.
Nguyen
Viet-Anh
VA
Wang
Tao
T
Tipping
Alex
A
Melo
Junia V
JV
Kufe
Donald
D
Austin
David J
DJ
Deisseroth
Albert
A
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005663:Furans / Q000737:chemistry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000480:Alkynes; D001549:Benzamides; D005663:Furans; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C524138:methyl 4-(2-naphthylamino)-4-oxo-3-butynoate; C524139:methyl 4-(4-phenoxyphenylamino)-4-oxo-3-butynoate; C524137:methyl 4-(cyclohexylamino)-4-oxo-3-butynoate; D005680:gamma-Aminobutyric Acid; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases