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AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.
Identification of Src-specific phosphorylation site on focal adhesion kinase: dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior.
The data show that Src kinase activity is required for adhesion turnover associated with cell migration in cancer cells and that, in addition to the catalytic activity, Src also acts as an adaptor to recruit other kinases that can phosphorylate key substrates including FAK.
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
Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells, and 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.
Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.
The low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P.
Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases
Investigating the role of Src family kinases (SFKs) in VEGF-mediated signalling in human colorectal carcinoma (CRC) cell lines suggests that VEGFR-1 promotes migration of tumour cells through a Src-dependent pathway linked to activation of focal adhesion components that regulate this process.
Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance.
  • M. Azam, V. Nardi, +11 authors G. Daley
  • Biology, Medicine
    Proceedings of the National Academy of Sciences…
  • 13 June 2006
In vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib and provides a rationale for combining conformation specific inhibitors to suppress resistance.
AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream
The results suggest that Src inhibitors affect biological properties of tumor progression and may be useful as cancer therapeutic agents in more advanced disease.
Anti-proliferative activity of the mTOR inhibitor AP23573 in combination with cytotoxic and targeted agents
3887 Background: AP23573 is a novel non-prodrug analog of rapamycin that inhibits mTOR signalling in tumors, leading to cell cycle arrest, tumor cell shrinkage and inhibition of angiogenesis. We have
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.
A novel series of five and six membered monocycles are explored as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib and displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant.
Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity.
The discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity and inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, and exhibits bone-targeting properties based on a hydroxyapatite adsorption assay.