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.citation | Cohen, Nicole. 2012. Selective Small Molecule Targeting of Anti-Apoptotic MCL-1. Doctoral dissertation, Harvard University. | en_US |
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 |