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1.
Dr. Jaebong Jang Dr. Ciric To Dr. Dries J. H. De Clercq Dr. Eunyoung Park Charles M. Ponthier Bo Hee Shin Mierzhati Mushajiang Dr. Radosław P. Nowak Dr. Eric S. Fischer Dr. Michael J. Eck Dr. Pasi A. Jänne Dr. Nathanael S. Gray 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(34):14589-14597
Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR. 相似文献
2.
Radosław Bonikowski Józef Kula Anna Bujacz Anna Wajs-Bonikowska Małgorzata Zakłos-Szyda Stanisław Wysocki 《Tetrahedron: Asymmetry》2012,23(14):1038-1045
Ten enantiomerically pure hydroindene-derived compounds obtained by the transformation of (+)-carotol, the main constituent of carrot seed essential oil, were examined for their ability to inhibit the growth of myeloid leukaemia (HL-60) cancer cell lines. All compounds showed significant activity, which was comparable to the most active volatile organic compounds, such as trans–trans-farnesol, citral and nerolidol. Based on the bioactivity and molecular modelling, a 3D QSAR pharmacophore model was generated. 相似文献
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We give necessary and sufficient conditions for the (bounded) law of the iterated logarithm for U-statistics in Hilbert spaces. As a tool we also develop moment and tail estimates for canonical Hilbert-space valued U-statistics of arbitrary order, which are of independent interest.
R. Adamczak’s research partially supported by MEiN Grant 2 PO3A 019 30.
R. Latała’s research partially supported by MEiN Grant 1 PO3A 012 29. 相似文献
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Starosta R Puchalska M Cybińska J Barys M Mudring AV 《Dalton transactions (Cambridge, England : 2003)》2011,40(11):2459-2468
The luminescent complexes of triphenylphosphine and two interesting aminomethylphosphines: P(CH(2)N(CH(2)CH(2))(2)NCH(3))(3) and P(CH(2)N(CH(2)CH(2))(2)O)(3) with copper(I) iodide and 2,9-dimethyl-1,10-phenanthroline (dmp): [CuI(dmp)PPh(3)], [CuI(dmp)P(CH(2)N(CH(2)CH(2))(2)NCH(3))(3)] and [CuI(phen)P(CH(2)N(CH(2)CH(2))(2)O)(3)] are presented in this work. These complexes were characterized in solution by means of NMR spectroscopy and their structures were crystallographically determined in the solid state. All complexes crystallize as the discrete dimers bound by π-stacking interactions between dmp rings. The coordination geometry about the Cu(I) centre is pseudo-tetrahedral showing small flattening and large rocking distortions. The investigated compounds exhibit intense orange photoluminescence in the solid state (emission peaks at r.t.: λ(max) = 588-592 nm; τ = 1.7-2.2 and 6.4-10.0 μs; at 77 K: λ(max) = 605-612 nm; τ = 4.8-6.5 and 32-47 μs), which is several orders higher than the luminescence of the analogous complexes with 1,10-phenanthroline (phen). Electronic and structural properties of the [CuI(dmp/phen)PR(3)] complexes were characterized using DFT methods to interpret their photophysics. On the basis of TDDFT calculations the broad CT bands observed in UV-Vis spectra are interpreted as the two mixed transitions from σ(CuI) bond with a small admixture of σ(CuP) bond to π* phen or dmp ligand: (MX,MPR(3))LCT, while the emissions most probably occur from two triplet states which are in thermal equilibrium. 相似文献
7.
Advanced SPE with molecularly imprinted polymers (MIP) was used in this study. A noncovalent imprinting approach was applied to separate 17β‐estradiol, estriol, and estrone from water samples. Polymer material was prepared by bulk polymerization with methacrylic acid as a functional monomer, divinylbenzene and ethyleneglycol dimethacrylate as crosslinkers, and acetonitrile, acetonitrile/toluene (3:1, v/v) or isooctane/toluene (1:99, v/v) as a porogen. We also prepared an MIP film on a silica gel surface with methacrylic acid and ethyleneglycol dimethacrylate as monomers and acetonitrile as a solvent. Qualitative and quantitative hormone analyses were carried out by HPLC with various detection techniques, including UV/visible spectroscopic detection (diode array detection) and electrochemical detection (CoulArray). The results of the study indicate that MIP technology is an excellent method for the quality control of estrogens in environmental analyses with a low quantification limit for 17β‐estradiol of around 26 (diode array detection) and 0.25 ng/mL (electrochemical detection). The proposed method was found to be suitable for routine determinations of the analyzed compound in environmental laboratories. 相似文献
8.
Lisiecki R Solarz P Dominiak-Dzik G Ryba-Romanowski W Łukasiewicz T 《Optics letters》2010,35(23):3940-3942
Optical spectra and luminescence decay curves were measured for thulium-doped YVO(4), GdVO(4), and LuVO(4) single crystals as a function of temperature in the 300-670 K temperature region. In spite of structural similarity, the three systems studied display significantly different transition intensities and nonradiative relaxation rates. It was found, in particular, that the peak value of the pump band absorption intensity diminishes by about 30% for Tm:YVO(4) and Tm:GdVO(4), and the effective emission cross section for the laser transition of Tm(3+) diminishes by a factor of 2 roughly when temperature increases from 300 to 500 K. An unusually small quantum efficiency of the upper laser level in Tm:LuVO(4) has been derived from the analysis of luminescence decay curves. 相似文献
9.
Piotr Przybylski Marcin Kwit Krystian Pyta Radosław Pankiewicz Grzegorz Schroeder Jacek Gawroński Bogumil Brzezinski 《Tetrahedron: Asymmetry》2010,21(8):973-981
Gossypol Schiff base with (R)-(+)-2-amino-3-benzyloxy-1-propanol 1 was synthesised and resolved by HPLC method into diastereomers to study their atropisomerisation process. The spectroscopic analysis performed by one- and two-dimensional NMR, UV–vis and FT-IR methods indicated that the compound exists in solution as an enamine-oxo tautomer. The ECD measurements and TD-DFT calculations allowed us to unambiguously determine the configuration about the axially chiral biaryl moiety of 1. The conditions of the atropisomerisation processes of diastereopure gossypol Schiff bases (SAX,R)-1 and (RAX,R)-1 were determined on the basis of ECD and NMR measurements. Exposure of the diastereomers of 1 to sunlight and to the light at λ = 254 nm significantly accelerated the atropisomerisation when compared to its rate in the dark. 相似文献
10.
Pawe? Niedzia?kowski Tadeusz Ossowski Rados?aw Majewski Zdzis?awa Nowakowska Grzegorz Schroeder 《Monatshefte für Chemie / Chemical Monthly》2011,89(3):1121-1129