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.
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. wei-sheng.huang@ariad.com
Wei-Sheng
WS
Huang
Chester A
CA
Metcalf
Raji
R
Sundaramoorthi
Yihan
Y
Wang
Dong
D
Zou
R Mathew
RM
Thomas
Xiaotian
X
Zhu
Lisi
L
Cai
David
D
Wen
Shuangying
S
Liu
Jan
J
Romero
Jiwei
J
Qi
Ingrid
I
Chen
Geetha
G
Banda
Scott P
SP
Lentini
Sasmita
S
Das
Qihong
Q
Xu
Jeff
J
Keats
Frank
F
Wang
Scott
S
Wardwell
Yaoyu
Y
Ning
Joseph T
JT
Snodgrass
Marc I
MI
Broudy
Karin
K
Russian
Tianjun
T
Zhou
Lois
L
Commodore
Narayana I
NI
Narasimhan
Qurish K
QK
Mohemmad
John
J
Iuliucci
Victor M
VM
Rivera
David C
DC
Dalgarno
Tomi K
TK
Sawyer
Tim
T
Clackson
William C
WC
Shakespeare
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