Browsing by Author "Papatzimas, James W"

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    Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1)
    (2020-09-14) Papatzimas, James W; Derksen, Darren J.; Ling, Chang-Chun; Bahlis, Nizar J.; MacCallum, Justin L.; Pierce, Joshua G.
    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.