40899-93-2Relevant articles and documents
Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
Wang, Ziqian,Xu, Wenjie,Song, Ting,Guo, Zongwei,Liu, Lu,Fan, Yudan,Wang, Anhui,Zhang, Zhichao
, (2017/01/11)
Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki = 0.48 μM by fluorescence polarization) over Bcl-2 (Ki = 3.6 μM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
BINHIBITORS OF HEPATITIS B VIRUS CONVALENTLY CLOSED CIRCULAR DNA FORMATION AND THEIR METHOD OF USE
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, (2013/09/12)
Pharmaceutical compositions of the invention comprise covalently closed circular DNA formation inhibitors having a disease-modifying action in the treatment of diseases associated with the formation of covalently closed circular DNA that include hepatitis B infection, and any disease involving formation of covalently closed circular DNA.
Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase
Mahboobi, Siavosh,Uecker, Andrea,Sellmer, Andreas,Cénac, Christophe,H?cher, Heymo,Pongratz, Herwig,Eichhorn, Emerich,Hufsky, Harald,Trümpler, Antje,Sicker, Marit,Heidel, Florian,Fischer, Thomas,Stocking, Carol,Elz, Sigurd,B?hmer, Frank-D.,Dove, Stefan
, p. 3101 - 3115 (2007/10/03)
FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid leukemia (AML). Recently, bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity, 35 novel derivatives were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors 98 and 102 show IC 50 values of 0.06 and 0.04 μM, respectively, and 1 order of magnitude lower PDGFR inhibiting activity. The derivatives 76 and 82 are 20- to 40-fold PDGFR selective. Docking at the recent FLT3 structure suggests a bidentate binding mode with the backbone of Cys-694. Activity and selectivity can be related to interactions of one indole moiety with a Hydrophobic pocket including Phe-691, the only different binding site residue (PDGFR Thr-681). Compound 102 inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts.