Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1)

Papatzimas, James W

Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1)

dc.contributor.advisor	Derksen, Darren J.
dc.contributor.author	Papatzimas, James W
dc.contributor.committeemember	Ling, Chang-Chun
dc.contributor.committeemember	Bahlis, Nizar J.
dc.contributor.committeemember	MacCallum, Justin L.
dc.contributor.committeemember	Pierce, Joshua G.
dc.date	Fall Convocation
dc.date.accessioned	2022-11-15T17:42:49Z
dc.date.embargolift	2022-09-14
dc.date.issued	2020-09-14
dc.description.abstract	Protein–protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. However, these kinds of protein interactions are difficult to perturb using traditional medicinal chemistry strategies. This has given rise to the development of a new method of addressing disease related proteins known as targeted protein degradation (TPD). TPD employs heterobifunctional small molecules which are capable of recruiting the cell’s natural recycling machinery, the ubiquitin proteasome system (UPS), and inducing proximity between this natural degradation machinery and a protein of interest (POI) to promote proteasomal degradation of the protein into its amino acid subunits. An ideal PPI-based target is the anti-apoptotic protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma (MM) where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy leads to an increase of MCL1 protein expression, a detrimental effect for several diseases. MCL1 has also been a challenging biological target to inhibit due to the prolific on-target cardiotoxicity associated with global MCL1 inhibition or knockdown.This work showcases the development of the first in class heterobifunctional small molecules capable of selectively targeting MCL1 through TPD methodology, leading to successful degradation. A synthesis program was embarked upon where chemical probes and cellular assay-guided structure activity relationship (SAR) studies motivated the optimization of these degrader compounds. We have confirmed the involvement of the E3 ubiquitin ligase CUL4A–DDB1 cereblon (CRBN) ubiquitination pathway through rigorous UPS checkpoint validation, making these MCL1 degraders a first step toward a new class of antiapoptotic B-cell lymphoma 2 (BCL2) family protein degraders.
dc.identifier.citation	Papatzimas, J. W. (2020). Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1) (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	http://hdl.handle.net/1880/115463
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/40430
dc.language.iso	en	en
dc.language.iso	English
dc.publisher.faculty	Graduate Studies	en
dc.publisher.faculty	Science
dc.publisher.institution	University of Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.	en
dc.subject	Protein Degradation
dc.subject	Ubiquitin Proteasome System
dc.subject	MCL1
dc.subject	Heterobifunctional Small Molecule Protein Degrader
dc.subject.classification	Chemistry--Organic
dc.subject.classification	Chemistry--Pharmaceutical
dc.subject.classification	Biology--Molecular
dc.subject.classification	Health Sciences--Oncology
dc.title	Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1)
dc.type	doctoral thesis
thesis.degree.discipline	Chemistry
thesis.degree.grantor	University of Calgary	en
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)