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41.
Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor 下载免费PDF全文
Dr. Jaebong Jang Dr. Jieun Son Dr. Eunyoung Park Dr. Takayuki Kosaka Dr. Jamie A. Saxon Dr. Dries J. H. De Clercq Dr. Hwan Geun Choi Dr. Junko Tanizaki Dr. Michael J. Eck Dr. Pasi A. Jänne Dr. Nathanael S. Gray 《Angewandte Chemie (International ed. in English)》2018,57(36):11629-11633
Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non‐small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co‐crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4‐fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient‐derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors. 相似文献
42.
In this article we study maximal operators related to differentiation bases. In particular, we find a sufficient condition
for the integrability of the maximal function. This complements earlier results of Hardy and Littlewood, de Guzmán and Kita.
We also give a geometric application of the result. 相似文献
43.
Hulkko E Ahokas J Lindgren J Myllyperkiö P Pettersson M 《The Journal of chemical physics》2012,136(17):174501
In the present work, we have studied ion-pair states of matrix-isolated I(2) with vacuum-UV absorption and UV-vis-NIR emission, where the matrix environment is systematically changed by mixing Kr with Xe, from pure Kr to a more polarizable Xe host. Particular emphasis is put on low doping levels of Xe that yield a binary complex I(2)-Xe, as verified by coherent anti-Stokes Raman scattering (CARS) measurements. Associated with interaction of I(2) with Xe we can observe strong new absorption in vacuum-UV, redshifted 2400 cm(-1) from the X → D transition of I(2). Observed redshift can be explained by symmetry breaking of ion-pair states within the I(2)-Xe complex. Systematic Xe doping of Kr matrices shows that at low doping levels, positions of I(2) ion-pair emissions are not significantly affected by complexation with Xe, but simultaneous increase of emissions from doubly spin-excited states indicates non-radiative relaxation to valence states. At intermediate doping levels ion-pair emissions shift systematically to red due to change in the average polarizability of the environment. We have conducted spectrally resolved ultrafast pump-probe ion-pair emission studies with pure and Xe doped Kr matrices, in order to reveal the influence of Xe to I(2) dynamics in solid Kr. Strikingly, relaxed emission from the ion-pair states shows no indication of complex presence. It further indicates that the complex escapes detection due to a non-radiative relaxation. 相似文献
44.
Tuulia Tynkkynen Mika Tiainen Pasi Soininen Reino Laatikainen 《Analytica chimica acta》2009,648(1):105-95
In this study, a protocol for pH determination from D2O samples using 1H NMR pH indicator compounds was developed and assessed by exploring the pH-dependency of 13 compounds giving pH-dependent 1H NMR signals. The indicators cover the pH range from pH* 0 to 7.2. Equations to transform the indicator chemical shifts to pH estimates are given here for acetic acid, formic acid, chloroacetic acid, dichloroacetic acid, creatine, creatinine, glycine, histidine, 1,2,4-triazole, and TSP (2,2,3,3-tetradeutero-3-(trimethylsilyl)-propionic acid). To characterize the method in presence of typical solutes, the effects of common metabolites, albumin and ionic strength were also evaluated. For the ionic strengths, the effects were also modelled. The experiments showed that the use of pH sensitive 1H NMR chemical shifts allows the pH determination of typical metabolite solutions with accuracy of 0.01-0.05 pH units. Also, when the ionic strength is known with accuracy better than 0.1 mol dm−3 and the solute concentrations are low, (the NMR estimate of pH) can be assumed to be within 0.05 pH units from potentiometrically determined pH. 相似文献
45.
Teija Niittymäki Ekaterina Burakova Evelina Laitinen Anna Leisvuori Pasi Virta Harri Lönnberg 《Helvetica chimica acta》2013,96(1):31-43
2‐(3,5‐Bis{[1,5,9‐tris(trifluoroacetyl)‐1,5,9‐triazacyclododecan‐3‐yloxy]methyl}phenoxy)ethanol was synthesized and converted to a O‐(2‐cyanoethyl)‐N,N‐diisopropylphosphoramidite building block, 12 . 2′‐O‐Methyl oligoribonucleotides incorporating a 2‐[(2S,4S,5R)‐4‐hydroxy‐5‐(hydroxymethyl)tetrahydrofuran‐2‐yl)ethyl 4‐oxopentanoate or a 2‐{2‐[2‐({[(2R,4S,5R)‐4‐hydroxy‐5‐(hydroxymethyl)tetrahydrofuran‐2‐yl]acetyl}amino)ethoxy]ethoxy}ethyl 4‐oxopentanoate non‐nucleosidic unit close to the 3′‐terminus were assembled on a solid support, the 4‐oxopentanoyl protecting groups were removed by treatment with hydrazinium acetate on‐support, and 12 was coupled to the exposed OH function. The deprotected conjugates were purified by HPLC, and their ability to cleave a complementary RNA containing either uridine or some other nucleoside at the potential cleaving site was compared. Somewhat unexpectedly, conjugation to an oligonucleotide did not enhance the catalytic activity of the Zn2+? bis(azacrown) complex and virtually abolished its selectivity towards the uridine sites. 相似文献
46.
Characteristics of the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal poststimulus undershoot in the visual cortex were studied at varying levels of arterial blood oxygen saturation (Ysat). Undershoot with an amplitude of -0.6+/-0.2% appeared after positive BOLD response (+1.7+/-0.5%) under control conditions. Cerebral blood volume (CBV), as determined with vascular-space-occupancy-dependent fMRI, increased by 26-43% during the positive BOLD peak, but the CBV proceeded at baseline level during the BOLD poststimulus undershoot. Mild hypoxic hypoxia (Ysat ranging from 0.82 to 0.89) had no effect on the amplitude or duration of poststimulus undershoot in activated BOLD pixels. Hypoxia did not influence CBV during the BOLD poststimulus undershoot. In contrast, the positive BOLD signal at the level of all activated pixels was smaller in hypoxia than in normoxia. The present results show that the BOLD poststimulus undershoot is not influenced by curtailed oxygen availability and that, during the undershoot, CBV is not different from resting state. 相似文献
47.
48.
49.
Two novel peptide scaffolds, viz. cyclo[(N(alpha)-Alloc)Dpr-beta-Ala-(N(alpha)-Fmoc)Dpr-beta-Ala] (1) and cyclo[(N(alpha)-Alloc)Dpr-alpha-azido-beta-aminopropanoyl-(N(alpha)-Fmoc)Dpr-beta-Ala] (2), composed of orthogonally protected 2,3-diaminopropanoyl (Dpr) and beta-alanyl residues, have been described. Fmoc chemistry on a backbone amide linker derivatized resin has been used for the chain assembly. Selective removal of the 4-methyltrityl (Mtt) and 1-methyl-1-phenylethyl protections (PhiPr) exposes the beta-amino and carboxyl terminus, respectively, and on-resin cyclization then gives the desired orthogonally protected cyclo-beta-tetrapeptides (1 and 2). The alpha-amino groups, bearing the Fmoc and Alloc protections and the azide mask, allow stepwise orthogonal derivatization of these solid-supported cyclo-beta-tetrapeptide cores (1 and 2). This has been demonstrated by attachments of various sugar units [viz., acetyl- or toluoyl-protected carboxymethyl alpha-d-glycopyranosides (13-15) and methyl 6-O-(4-nitrophenoxycarbonyl)-alpha-d-glycopyranosides (22-24)] to obtain diverse di- and trivalent glycoclusters (33-42). Acidolytic release (TFA) from the support, followed by conventional NaOMe-catalyzed transesterification (33-40) or hydrazine-induced acyl substitution in DMF (41 and 42), gives the fully deprotected clusters (43-52) as final products. 相似文献
50.
Holappa J Nevalainen T Safin R Soininen P Asplund T Luttikhedde T Másson M Järvinen T 《Macromolecular bioscience》2006,6(2):139-144
Novel synthesis methods for the preparation of quaternary piperazine derivatives of chitosan were developed. Quaternary ammonium moiety can be selectively inserted into either one or both of the piperazine nitrogens, yielding structurally uniform chitosan derivative structures. Water-soluble end products were thoroughly characterized with FT-IR, 1H NMR, 13C NMR and 2D 1H-13C HSQC NMR. The molecular weights of the end products were determined by GPC with triple detection. 相似文献