Identifying Therapeutic Vulnerabilities in Cancers Driven by the Oncogenic Transcription Factor STAT3

Identifying Therapeutic Vulnerabilities in Cancers Driven by the Oncogenic Transcription Factor STAT3

Identifying Therapeutic Vulnerabilities in Cancers Driven by the Oncogenic Transcription Factor STAT3 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Heppler, Lisa Nicole. 2019. Identifying Therapeutic Vulnerabilities in Cancers Driven by the Oncogenic Transcription Factor STAT3. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42013162 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA ! "#$%&'()'%*!+,$-./$0&'1!203%$-.4'3'&'$5!'%!6.%1$-5!7-'8$%!4)!&,$!9%1:*$%'1! +-.%51-'/&':%!;.1&:-!<+=+>! ! ! =!#'55$-&.&':%!/-$5$%&$#! 4)! ?'5.!@'1:3$!A$//3$-! &:! +,$!7'8'5':%!:(!B$#'1.3!<1'$%1$5! 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'%!H>=!,0C.%!('4-:5.-1:C.!1$335!OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOLJ[! I4BB*+8+/%'*!)'#*+!HL@L!+:/!\KK!/-:&$'%5!#$5&.4'3'R$#!4)!/)-'C$&,.C'%$!! '%!H>=!,0C.%!('4-:5.-1:C.!1$335!OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOL>^! I4BB*+8+/%'*!)'#*+!HLHL!DZ+TE6Z!/-'C$-!5$D0$%1$5!OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOL]M! vi 01$%!,-!2134&+$! 2134&+!=L=L!<&-01&0-.3!.%#!(0%1&':%.3!:8$-8'$U!:(!&,$!5'*%.3!&-.%5#01$-!.%#! .1&'8.&:-!:(!&-.%51-'/&':%!X<+=+Y!(.C'3)!:(!&-.%51-'/&':%!(.1&:-5 ...........................4! Figure 2.1. High-throughput chemical library screen identifies pyrimethamine as a specific STAT3 inhibitor .......................................................................................19! Figure 2.2. Pyrimethamine inhibits STAT3 transcriptional activity without decreasing STAT3 phosphorylation or nuclear localization ..................................22! 2134&+!@LHL!_$%$-.&':%!:(!B7=TBGT]W^!5043'%$!-$5'5&.%&!&:!&,$!'%,'4'&:-)!$(($1&5! :(!/)-'C$&,.C'%$ ...................................................................................................26! 2134&+!@LJL!G.5.3!.%#!1)&:Q'%$T5&'C03.&$#!<+=+>!&)-:5'%$!/,:5/,:-)3.&':%!.-$! .4%:-C.3!'%!/)-'C$&,.C'%$T-$5'5&.%&!]W^!1$335 .....................................................30! 2134&+!@LMO!E)-'C$&,.C'%$T-$5'5&.%&!]W^!1$335!,.8$!#$1-$.5$#!4.5.3!<+=+>!! .1&'8'&) ....................................................................................................................34! 2134&+!@LDL!6:C/$%5.&:-)!.1&'8.&':%!:(!<+=+L!:-!<+=+\!#:$5!%:&!.//$.-!&:!4$! &,$!#-'8$-!:(!-$5'5&.%1$!'%!/)-'C$&,.C'%$T-$5'5&.%&!]W^!1$335 ................................38! 2134&+!@LNL!G6?W!3:55!-$1./'&03.&$5!&,$!*$%$!$S/-$55':%!.%#!-$5'5&.%1$!/,$%:&)/$! :(!/)-'C$&,.C'%$T-$5'5&.%&!]W^!1$335 .....................................................................42! 2134&+!@LOO!63:%$5!#$-'8$#!(-:C!/)-'C$&,.C'%$T-$5'5&.%&!]W^!1$335!.-$!-$5'5&.%&!&:! /)-'C$&,.C'%$!.%#!#$C:%5&-.&$!5'C'3.-!*$%$!$S/-$55':%!/.&&$-%5 ........................46! 2134&+!@LPO!G6?W!.%#!<+=+>!4'%#!C.%)!:(!&,$!5.C$!&.-*$&!*$%$5 .....................49! 2134&+!@L=QO!E-:/:5$#!C:#$3!(:-!/)-'C$&,.C'%$TC$#'.&$#!<+=+>!'%,'4'&':% ....55! 2134&+!HL=L!E"<=!.55.)!'#$%&'('$5!7A;Z!.5!.!#'-$1&!C:3$103.-!&.-*$&!:(! /)-'C$&,.C'%$ .......................................................................................................70! 2134&+!HL@L!E)-'C$&,.C'%$!'%,'4'&5!,0C.%!7A;Z!.1&'8'&) ..................................75! vii 2134&+!HLHL!7A;Z!3:55!#$1-$.5$5!4.5.3!/<+=+>!3$8$35I!1)&:Q'%$T5&'C03.&$#! <+=+>!&-.%51-'/&':%.3!.1&'8'&)I!.%#!<+=+>!&.-*$&!*$%$!$S/-$55':% .....................80! 2134&+!HLJL!B$&,:&-$S.&$I!.!Q%:U%!'%,'4'&:-!:(!,0C.%!7A;ZI!.35:!'%,'4'&5!<+=+>! &-.%51-'/&':%.3!.1&'8'&) ...........................................................................................84! 2134&+!HLML!7A;ZT#$/$%#$%&!C$&,)3.&':%!-$.1&':%5!#:!%:&!C$#'.&$!&,$!<+=+>T '%,'4'&:-)!$(($1&5!:(!/)-'C$&,.C'%$ .......................................................................89!

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