Recent Advances in Small Molecule PROTACs for the Treatment of Cancer

Li, Wen; Elhassan, Reham M.; Hou, Xuben; Fang, Hao

doi:10.2174/0929867327666201117141611

Cited by 11 publications

(9 citation statements)

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“…However, drug resistance and on-target toxicities remain a problem 197 , 198 . Several PROTACs, including ARV-110 and ARV-471, which target the androgen receptor and oestrogen receptor, displayed promising results in cell lines and mouse models for prostate cancer and breast cancer, respectively, and have thus entered clinical trials 199 . Multiple variations of PROTACs are currently being developed to significantly expand the pool of potential substrates, such as autophagy-targeting chimeras 200 , autophagosome-tethering compounds 201 , lysosome-targeting chimeras 202 and antibody-based PROTACs 203 , with the last two enabling the degradation of secreted and cell surface proteins.…”

Section: Concluding Remarks and Future Challengesmentioning

confidence: 99%

An expanded lexicon for the ubiquitin code

Đikić

Schulman

2022

Nat Rev Mol Cell Biol

107

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Our understanding of the ubiquitin code has greatly evolved from conventional E1, E2 and E3 enzymes that modify Lys residues on specific substrates with a single type of ubiquitin chain to more complex processes that regulate and mediate ubiquitylation. In this Review, we discuss recently discovered endogenous mechanisms and unprecedented pathways by which pathogens rewrite the ubiquitin code to promote infection. These processes include unconventional ubiquitin modifications involving ester linkages with proteins, lipids and sugars, or ubiquitylation through a phosphoribosyl bridge involving Arg42 of ubiquitin. We also introduce the enzymatic pathways that write and reverse these modifications, such as the papain-like proteases of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. Furthermore, structural studies have revealed that the ultimate functions of ubiquitin are mediated not simply by straightforward recognition by ubiquitin-binding domains. Instead, elaborate multivalent interactions between ubiquitylated targets or ubiquitin chains and their readers (for example, the proteasome, the MLL1 complex or DOT1L) can elicit conformational changes that regulate protein degradation or transcription. The newly discovered mechanisms provide opportunities for innovative therapeutic interventions for diseases such as cancer and infectious diseases.

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Section: Concluding Remarks and Future Challengesmentioning

confidence: 99%

An expanded lexicon for the ubiquitin code

Đikić

Schulman

2022

Nat Rev Mol Cell Biol

107

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“…Many PROTACs targeting different proteins have been developed in recent years, while several PROTACs have been already in a Phase I clinical trial. − Among HDAC members, SIRT2, an NAD-dependent HDAC, was targeted using PROTAC in 2018 . The first HDAC6 PROTAC was developed by the Tang group in 2018, which is derived from their previously reported pan-HDAC inhibitors .…”

mentioning

confidence: 99%

Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6

Cao

Lin

et al. 2021

ACS Chem. Biol.

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Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.

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“…A covalent inhibitor that forms a bond with a tyrosine was recently successfully placed on Ral which is almost identical to Ras GTPases 144 . Since covalent drugs are long‐lived, protein degradation through covalently attached proteolysis targeting chimeras (PROTACs) are being pursued 145–150 …”

Section: Protein Structure‐based Moa Drug Classificationmentioning

confidence: 99%

“…144 Since covalent drugs are long-lived, protein degradation through covalently attached proteolysis targeting chimeras (PROTACs) are being pursued. [145][146][147][148][149][150] 4 | PROTEIN ENSEMBLES, DRIVER MUTATIONS, AND DRUGS Biological functions are regulated by conformational states. Since proteins are highly dynamic molecules, evaluation of the protein structural ensembles is superior to that of a single state.…”

Section: Protein Structure-based Moa Drug Classificationmentioning

confidence: 99%

Mechanism of activation and the rewired network: New drug design concepts

Nussinov

Zhang

Maloney

et al. 2021

Medicinal Research Reviews

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Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.

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Recent Advances in Small Molecule PROTACs for the Treatment of Cancer

Cited by 11 publications

References 0 publications

An expanded lexicon for the ubiquitin code

An expanded lexicon for the ubiquitin code

Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6

Mechanism of activation and the rewired network: New drug design concepts

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