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      The Activity of Novel BCR-ABL Small-Molecule Degraders Containing Pyrimidine Rings and Their Role in Overcoming Drug Resistance

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          Abstract

          Inducing protein degradation by proteolysis-targeting chimeras (PROTACs) has gained tremendous momentum in the field for its promise in the discovery and development of new therapies. Based on our previously reported PROTAC BCR-ABL degraders, we designed and synthesized additional 4 PROTAC compounds with a novel linker that contains pyrimidine rings. Molecular and cellular studies have shown that different linkers affect the degradation activity of small-molecule degraders on the target protein of BCR-ABL. We screened out a lead compound, DMP11, with stable physicochemical properties and high activity. Preliminary evaluation of its pharmacodynamics in vitro model showed that it has a good inhibitory effect on imatinib-resistant chronic myeloid leukemia cell lines, as has been shown in animal models. Our preliminary research into the mechanism of DMP11 found that DMP11 can overcome drug resistance by simultaneously inhibiting the targets of BCR-ABL and SRC-family kinase (SFK).

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          Most cited references42

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          Catalytic in vivo protein knockdown by small-molecule PROTACs.

          The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
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            Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.

            BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.
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              Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

              The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.
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                Author and article information

                Contributors
                Journal
                J Oncol
                J Oncol
                jo
                Journal of Oncology
                Hindawi
                1687-8450
                1687-8469
                2022
                30 October 2022
                : 2022
                : 4056398
                Affiliations
                1School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China
                2Zhejiang Provincial Laboratory of Experimental Animal's and Nonclinical Laboratory Studies, Hangzhou, Zhejiang, China
                3School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
                Author notes

                Academic Editor: Junmin Zhang

                Author information
                https://orcid.org/0000-0002-8172-3547
                https://orcid.org/0000-0002-4287-6858
                https://orcid.org/0000-0002-2742-1687
                https://orcid.org/0000-0002-2223-3142
                https://orcid.org/0000-0003-3408-3142
                https://orcid.org/0000-0002-7955-7455
                https://orcid.org/0000-0003-3326-8380
                https://orcid.org/0000-0001-8274-0894
                Article
                10.1155/2022/4056398
                9637472
                0bc303f6-e7f0-4c60-9f3e-bb3bfa0b96dc
                Copyright © 2022 Xu Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 June 2022
                : 28 September 2022
                : 17 October 2022
                Funding
                Funded by: Department of Education of Zhejiang Province
                Award ID: Y202146049
                Funded by: Department of Health of Zhejiang Province
                Award ID: 2021KY646
                Funded by: Health Commission of Zhejiang Province
                Award ID: 2020KY526
                Funded by: Department of Education of Zhejiang Province
                Award ID: Y202045350
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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