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AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
TLDR
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.
Probing the α‐Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations and Analysis
TLDR
Detailed all‐atom molecular dynamics simulations are used to study a series of stapled α‐helical peptides and find significant variation in local structural flexibility of the peptides with the position of the linker, which appears to be more closely related to the observed differences in activity than the absolute α‐ Helical stability.
4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.
TLDR
This Nle4, D-Phe7 synthetic analogue of alpha-MSH is a very porent melanotropin, 26 times as potent as alpha- MSH in the adenylate cyclase assay, and the resistance of the peptide to enzymatic degradation and its extraordinarily potent and prolonged biological activity should make this analogue ofalpha-MSh an important molecular probe for studying the melanotropic receptors of both normal and abnormal (melanoma) melanocytes.
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.
TLDR
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.
Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy
TLDR
Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein–protein interaction and may offer a viable modality for cancer therapy.
Substrate specificity of the protein tyrosine phosphatases.
TLDR
The results demonstrate that chemical features in the primary structure surrounding the dephosphorylation site contribute to PTPase substrate specificity and suggest that phosphate dianion is favored for substrate binding.
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
TLDR
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.
Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase 1B.
TLDR
Clear sequence specificity was revealed in the binding of proteins involved in the regulation of intracellular signaling by receptor tyrosine kinases in a concentration-dependent manner.
Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.
TLDR
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
TLDR
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.
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