6980-08-1Relevant articles and documents
Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy
Gavriil, Efthymios-Spyridon,Doukatas, Aris,Karampelas, Theodoros,Myrianthopoulos, Vassilios,Dimitrakis, Spyridon,Mikros, Emmanuel,Marakos, Panagiotis,Tamvakopoulos, Constantin,Pouli, Nicole
, p. 393 - 409 (2019/05/22)
Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23)displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23)was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.
IMIDAZOPYRIDINES AS INHIBITORS OF AURORA KINASE AND/OR FLT3
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Paragraph 00117; 00118, (2014/01/09)
The present invention relates to compounds of formula I: wherein R1 and R2 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof. The compounds of formula I are inhibitors of aurora kinase and/or FLT3. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which aurora kinase and/or FLT3 activity is implicated.
Optimization of imidazo[4,5- b ]pyridine-based kinase inhibitors: Identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia
Bavetsias, Vassilios,Crumpler, Simon,Sun, Chongbo,Avery, Sian,Atrash, Butrus,Faisal, Amir,Moore, Andrew S.,Brown, Nathan,Sheldrake, Peter W.,Bush, Katherine,Henley, Alan,Box, Gary,Valenti, Melanie,De Haven Brandon, Alexis,Raynaud, Florence I.,Workman, Paul,Eccles, Suzanne A.,Linardopoulos, Spiros,Blagg, Julian,Kosmopoulou, Magda,Bayliss, Richard
supporting information, p. 8721 - 8734,14 (2020/09/16)
Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin- 1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A Kd = 7.5 nM, Aurora-B K d = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.
