Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

He, Ming; Lv, Wenxing; Rao, Yu

doi:10.3389/fcell.2021.685106

Cited by 36 publications

(37 citation statements)

References 136 publications

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“…Some pharmaceutical or biotech companies (e.g., STORM Therapeutics, Accent Therapeutics, Gotham Therapeutics, and Genovel Biotech Corp.) have started to develop highly potent and selective small-molecule inhibitors that directly target m 6 A regulators such as METTL3, METTL14, FTO, and ALKBH5 [ 30 ]. In addition, PROTAC (proteolysis targeting chimera)-based or molecular glue-based inhibitors could be developed to selectively degrade dysregulated m 6 A regulatory proteins for cancer therapy [ 30 , 124 ]. Also, gene silencing using oligonucleotide-based therapeutics (ONTs), such as small interfering RNA (siRNA), antisense oligonucleotides, or decoy oligodeoxynucleotides, is a promising strategy for targeting m 6 A regulators in tumor cells and immune cells.…”

Section: Strategies and Challenges Of Targeting M 6 ...mentioning

confidence: 99%

Targeting the RNA m6A modification for cancer immunotherapy

et al. 2022

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N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

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Section: Strategies and Challenges Of Targeting M 6 ...mentioning

confidence: 99%

Targeting the RNA m6A modification for cancer immunotherapy

et al. 2022

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“…Specifically, PROTACs regulate the expression of the protein of interest at the posttranslational level by directing the targets to the cellular proteolytic machinery, such as the ubiquitin-proteasome pathway [242]. PROTAC technology makes druggable the traditional "unable to medicine" targets and has tremendous potential in overcoming drug resistance [241,243]. PROTACs comprise heterobifunctional compounds engineered to recruit the protein target to the E3 ubiquitin ligase for ubiquitination, and subsequently proteasomal degradation [244,245].…”

Section: Proteolysis Targeting Chimerasmentioning

confidence: 99%

“…Proteolysis Targeting Chimeras characteristic of small-inhibitor compounds is that they are designed, for example, to inhibit the catalytic activities of the protein target, while the potential non-catalytic functions are not affected. A new method of drug design implicates the complete protein target depletion by constructing proteolysis-targeting chimeras (PROTACs) that achieve the regulation of both enzymatic and non-enzymatic functions [241].…”

Section: Proteolysis Targeting Chimerasmentioning

confidence: 99%

“…PROTACs comprise heterobifunctional compounds engineered to recruit the protein target to the E3 ubiquitin ligase for ubiquitination, and subsequently proteasomal degradation [244,245]. The unique PROTACs mechanism of action provides several advantages, such as a catalytic mode of action instead of high equilibrium target occupancy, improving potency, enhancing selectivity compared with the initial promiscuous targeting warhead, persistent target protein depletion, and potential tissue-cellular selectivity, compared with conventional small-compound inhibitors [241]. Furthermore, because PROTACs exert an acute and reversible post-translational protein depletion, this technology offers better advantages than other genetic knockdown methodologies.…”

Section: Proteolysis Targeting Chimerasmentioning

confidence: 99%

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Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

et al. 2022

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The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.

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“…Technologies that lead to targeted protein degradation, such as proteolysis-targeting chimeras (PROTACs), protein-catalyzed capture agents (PCCs), and specific and nongenetic inhibitors of apoptosis protein-dependent protein erasers, have been successfully applied to develop novel kinase inhibitors [ 202 , 203 , 204 , 205 , 206 ]. For example, a PROTAC consisting of alisertib, a clinically used ATP-competitive inhibitor of AURKA [ 207 ], and thalidomide, which induces protein degradation via cereblon-containing ubiquitin ligase, results in proteolysis of AURKA and arrest of the cell cycle in MV4-11 human acute myeloid leukemia cells [ 5 ].…”

Section: Future Directionsmentioning

confidence: 99%

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Nishimura

Yamakawa

Shiromizu

et al. 2021

Cells

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Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.

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Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

Cited by 36 publications

References 136 publications

Targeting the RNA m6A modification for cancer immunotherapy

Targeting the RNA m6A modification for cancer immunotherapy

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

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