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Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up
Published on: March 26, 2018
From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
James W Papatzimas1, Evgueni Gorobets1, Ranjan Maity1
1Arnie Charbonneau Cancer Institute , University of Calgary , 3280 Hospital Drive NW , T2N 4Z6 Calgary , Alberta , Canada.
Abstract:
Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma 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 actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
Insights
Researchers developed novel proteolysis targeting chimeras (PROTACs) to degrade myeloid cell leukemia 1 (MCL1) protein, a key factor in cancer progression. This new approach offers a promising strategy for targeting antiapoptotic proteins in cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Protein-protein interactions (PPIs) are crucial in biological processes and represent significant therapeutic targets.
- Myeloid cell leukemia 1 (MCL1) is a prosurvival factor critical in cancers like multiple myeloma, with elevated levels correlating to disease progression.
- Current MCL1 inhibitors increase MCL1 protein levels, limiting therapeutic efficacy.
Purpose of the Study:
- To develop novel hetero-bifunctional small molecules targeting MCL1 for degradation.
- To establish a new class of antiapoptotic B-cell lymphoma 2 (BCL-2) family protein degraders.
Main Methods:
- Development of proteolysis targeting chimera (PROTAC) molecules designed to selectively target MCL1.
- Confirmation of the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway in PROTAC-mediated degradation.
Main Results:
- Successful degradation of MCL1 protein using the developed PROTACs.
- Demonstration of selective targeting of MCL1.
Conclusions:
- PROTACs offer a novel strategy for targeting and degrading MCL1, a key antiapoptotic protein.
- This work represents a significant step towards developing a new class of BCL-2 family protein degraders for cancer therapy.
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