Selective Small Molecule Targeting of Anti-Apoptotic MCL-1

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Selective Small Molecule Targeting of Anti-Apoptotic MCL-1

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dc.contributor.advisor Walensky, Loren David
dc.contributor.author Cohen, Nicole
dc.date.accessioned 2012-11-14T13:40:53Z
dc.date.issued 2012-11-14
dc.date.submitted 2012
dc.identifier.other http://dissertations.umi.com/gsas.harvard:10544 en
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9904005
dc.description.abstract BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. Anti-apoptotic members such as BCL-2, \(BCL-X_L\), and MCL-1 have been implicated in the initiation, progression, and chemoresistance of human cancer. Small molecules and peptides have successfully targeted the anti-apoptotic BCL-2/\(BCL-X_L\) groove that binds and sequesters pro-apoptotic BH3 death helices. Such compounds induce tumor cell apoptosis and are being advanced in clinical trials as promising next-generation cancer therapeutics. Notably, selective antagonists such as ABT-737 are highly effective at inducing apoptosis in BCL-2/\(BCL-X_L\)-dependent cancers but are rendered inactive by overexpression of MCL-1, a formidable chemoresistance protein that lies outside the molecule's binding spectrum. By screening a library of stabilized alpha-helices of BCL-2 domains (SAHBs), we previously discovered that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. Here, we deployed this chemically-constrained peptidic inhibitor of MCL-1, MCL-1 SAHB, in a competitive binding screen to identify selective small molecule inhibitors of MCL-1. Rigorous in vitro binding and functional assays were used to validate the compounds and their mechanisms of action, and most notably, MCL-1 inhibitor molecule 1 (MIM1) displayed exquisite selectivity in these assays. NMR analysis documented that MIM1 engages the canonical BH3-binding pocket of MCL-1. Importantly, MIM1 selectively triggers caspase 3/7 activation and apoptosis of a cancer cell line that is dependent on induced overexpression of MCL-1 but showed no activity in the isogenic cell line that is driven instead by overexpressed \(BCL-X_L\). Thus, a selective stapled peptide inhibitor of MCL-1 was successfully applied to identify a high fidelity small molecule inhibitor of MCL-1 that exhibits anti-cancer activity in the specific context of MCL-1 dependence. en_US
dc.language.iso en_US en_US
dash.license LAA
dc.subject biology en_US
dc.subject cellular biology en_US
dc.title Selective Small Molecule Targeting of Anti-Apoptotic MCL-1 en_US
dc.type Thesis or Dissertation en_US
dc.date.available 2012-11-14T13:40:53Z
thesis.degree.date 2012 en_US
thesis.degree.discipline Biological Chemistry and Molecular Pharmacology en_US
thesis.degree.grantor Harvard University en_US
thesis.degree.level doctoral en_US
thesis.degree.name Ph.D. en_US
dc.contributor.committeeMember Eck, Michael en_US
dc.contributor.committeeMember Coen, Donald en_US
dc.contributor.committeeMember Danial, Nika en_US
dc.contributor.committeeMember Kritzer, Joshua en_US

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