Matches in SemOpenAlex for { <https://semopenalex.org/work/W2277797998> ?p ?o ?g. }
- W2277797998 endingPage "292" @default.
- W2277797998 startingPage "273" @default.
- W2277797998 abstract "Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia." @default.
- W2277797998 created "2016-06-24" @default.
- W2277797998 creator A5005548997 @default.
- W2277797998 creator A5008043464 @default.
- W2277797998 creator A5009956168 @default.
- W2277797998 creator A5019039152 @default.
- W2277797998 creator A5033946508 @default.
- W2277797998 creator A5037456499 @default.
- W2277797998 creator A5041786396 @default.
- W2277797998 creator A5041935136 @default.
- W2277797998 creator A5043439976 @default.
- W2277797998 creator A5046354565 @default.
- W2277797998 creator A5052465794 @default.
- W2277797998 creator A5053783648 @default.
- W2277797998 creator A5071216632 @default.
- W2277797998 creator A5072343549 @default.
- W2277797998 creator A5073626775 @default.
- W2277797998 creator A5081341939 @default.
- W2277797998 creator A5085686400 @default.
- W2277797998 creator A5087270469 @default.
- W2277797998 date "2016-05-01" @default.
- W2277797998 modified "2023-09-26" @default.
- W2277797998 title "Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein" @default.
- W2277797998 cites W1544358611 @default.
- W2277797998 cites W1973433643 @default.
- W2277797998 cites W1973723375 @default.
- W2277797998 cites W1976499671 @default.
- W2277797998 cites W1977258127 @default.
- W2277797998 cites W1978244665 @default.
- W2277797998 cites W1983509869 @default.
- W2277797998 cites W1985494181 @default.
- W2277797998 cites W1986322598 @default.
- W2277797998 cites W1992365057 @default.
- W2277797998 cites W2000530224 @default.
- W2277797998 cites W2000677615 @default.
- W2277797998 cites W2009508949 @default.
- W2277797998 cites W2012835470 @default.
- W2277797998 cites W2019048640 @default.
- W2277797998 cites W2019402016 @default.
- W2277797998 cites W2027395744 @default.
- W2277797998 cites W2030029504 @default.
- W2277797998 cites W2032638890 @default.
- W2277797998 cites W2036677047 @default.
- W2277797998 cites W2038683465 @default.
- W2277797998 cites W2045744325 @default.
- W2277797998 cites W2047609201 @default.
- W2277797998 cites W2049225373 @default.
- W2277797998 cites W2059416155 @default.
- W2277797998 cites W2060002448 @default.
- W2277797998 cites W2060872117 @default.
- W2277797998 cites W2062496875 @default.
- W2277797998 cites W2067139663 @default.
- W2277797998 cites W2068962767 @default.
- W2277797998 cites W2069002336 @default.
- W2277797998 cites W2070753604 @default.
- W2277797998 cites W2080412910 @default.
- W2277797998 cites W2080903411 @default.
- W2277797998 cites W2083431520 @default.
- W2277797998 cites W2085419794 @default.
- W2277797998 cites W2091562724 @default.
- W2277797998 cites W2093663447 @default.
- W2277797998 cites W2094912923 @default.
- W2277797998 cites W2095453782 @default.
- W2277797998 cites W2100665941 @default.
- W2277797998 cites W2112020656 @default.
- W2277797998 cites W2113278680 @default.
- W2277797998 cites W2113703332 @default.
- W2277797998 cites W2115339329 @default.
- W2277797998 cites W2119316461 @default.
- W2277797998 cites W2123621979 @default.
- W2277797998 cites W2124047990 @default.
- W2277797998 cites W2126709547 @default.
- W2277797998 cites W2142098498 @default.
- W2277797998 cites W2143603753 @default.
- W2277797998 cites W2150048195 @default.
- W2277797998 cites W2150496578 @default.
- W2277797998 cites W2150680216 @default.
- W2277797998 cites W2153856953 @default.
- W2277797998 cites W2162774171 @default.
- W2277797998 cites W2165208382 @default.
- W2277797998 cites W2167690894 @default.
- W2277797998 cites W2169821755 @default.
- W2277797998 cites W2170306299 @default.
- W2277797998 cites W2171224722 @default.
- W2277797998 cites W2171268876 @default.
- W2277797998 cites W2321269681 @default.
- W2277797998 cites W2325448383 @default.
- W2277797998 cites W2326290971 @default.
- W2277797998 cites W2331882936 @default.
- W2277797998 cites W2340621314 @default.
- W2277797998 cites W4232872069 @default.
- W2277797998 cites W975708185 @default.
- W2277797998 doi "https://doi.org/10.1016/j.ejmech.2016.02.006" @default.
- W2277797998 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4811700" @default.
- W2277797998 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26985630" @default.
- W2277797998 hasPublicationYear "2016" @default.
- W2277797998 type Work @default.
- W2277797998 sameAs 2277797998 @default.