Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.

Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.

[1]  Wei-Sheng Huang,et al.  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. , 2010, Journal of medicinal chemistry.

[2]  T. Clackson,et al.  AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. , 2009, Cancer cell.

[3]  Tomoko Niwa,et al.  Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. , 2007, Leukemia research.

[4]  M. Avery,et al.  Addition of lithioimidazoles to isocyanates followed by Pd-coupling: access to 4-substituted imidazole-2,5-dicarboxamides , 2004 .

[5]  Rocco Piazza,et al.  Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[7]  J. Mestan,et al.  In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. , 2005, Cancer research.

[8]  Alex Matter,et al.  Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug , 2002, Nature Reviews Drug Discovery.

[9]  T. Clackson,et al.  Structural Mechanism of the Pan‐BCR‐ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance , 2011, Chemical biology & drug design.

[10]  Francisco Cervantes,et al.  Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. , 2006, The New England journal of medicine.

[11]  N. Gray,et al.  Broad spectrum alkynyl inhibitors of T315I Bcr-Abl. , 2010, Bioorganic & medicinal chemistry letters.

[12]  Donna Neuberg,et al.  Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. , 2005, Cancer cell.

[13]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[14]  G. Daley,et al.  9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation. , 2009, Journal of medicinal chemistry.