Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.
Huang
Wei-Sheng
WS
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. wei-sheng.huang@ariad.com
Metcalf
Chester A
CA
Sundaramoorthi
Raji
R
Wang
Yihan
Y
Zou
Dong
D
Thomas
R Mathew
RM
Zhu
Xiaotian
X
Cai
Lisi
L
Wen
David
D
Liu
Shuangying
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Romero
Jan
J
Qi
Jiwei
J
Chen
Ingrid
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Banda
Geetha
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Lentini
Scott P
SP
Das
Sasmita
S
Xu
Qihong
Q
Keats
Jeff
J
Wang
Frank
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Wardwell
Scott
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Ning
Yaoyu
Y
Snodgrass
Joseph T
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Broudy
Marc I
MI
Russian
Karin
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Zhou
Tianjun
T
Commodore
Lois
L
Narasimhan
Narayana I
NI
Mohemmad
Qurish K
QK
Iuliucci
John
J
Rivera
Victor M
VM
Dalgarno
David C
DC
Sawyer
Tomi K
TK
Clackson
Tim
T
Shakespeare
William C
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D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000401:mortality; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl