AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia.
Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.
Golemovic
Mirna
M
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Verstovsek
Srdan
S
Giles
Francis
F
Cortes
Jorge
J
Manshouri
Taghi
T
Manley
Paul W
PW
Mestan
Jürgen
J
Dugan
Margaret
M
Alland
Leila
L
Griffin
James D
JD
Arlinghaus
Ralph B
RB
Sun
Tong
T
Kantarjian
Hagop
H
Beran
Miloslav
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C498826:nilotinib