Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

Zhou, Haibin; Bai, Longchuan; Xu, Renqi; Zhao, Yujun; Chen, Jianyong; McEachern, Donna; Chinnaswamy, Krishnapriya; Wen, Bo; Dai, Lipeng; Kumar, Praveen; Yang, Chao‐Yie; Liu, Zhaomin; Wang, Mi; Liu, Liu; Meagher, Jennifer L.; Han, Yongtao; Sun, Duxin; Stuckey, Jeanne A.; Wang, Shaomeng

doi:10.1021/acs.jmedchem.9b01530

Cited by 158 publications

(115 citation statements)

References 41 publications

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“…In summary, this special issue offers an overview of different STAT3/5 targeting approaches in the context of multiple disease indications. Emerging drug design strategies and medicinal chemistry approaches, including methods to impair function [44] destabilize or degrade transcription factors [45][46][47], interfere with interaction partners and cofactors [48], block DNA binding [49], nuclear shuttling [41], or target specific subsets of cell types/microenvironment [50], initiated new concepts for broad views on targeting. Consequently, targeting oncogenic transcription factors of the STAT family, namely STAT3, STAT5A, and STAT5B as three distinct gene products are major funnels for gene regulatory processes, including chromatin remodeling.…”

Section: Discussionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Cancer

Araujo

Keserü

Gunning

et al. 2020

Cancers

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Section: Discussionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Cancer

Araujo

Keserü

Gunning

et al. 2020

Cancers

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“…Methylbestatin (12) and a higher-affinity derivative of LCL161 (13) are most commonly used to target cIAP. Nutlin-3 (14) has been used to target MDM2 of this is shown in foretinib-based degraders of the MAPK family developed by the Crews group. The c-Met tyrosine kinase inhibitor foretinib (17) is highly promiscuous: it binds to 133 different kinases with high affinity [55].…”

Section: Protac Warheadsmentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

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PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

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“…Wang and coworkers [88,89] developed a highly potent STAT3 inhibitor SI-109 and used it to develop a STAT3-targeting PROTAC SD-36 ( Fig. 7).…”

Section: Protacs Targeting Stat3mentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

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Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting~50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

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Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

Cited by 158 publications

References 41 publications

Targeting STAT3 and STAT5 in Cancer

Targeting STAT3 and STAT5 in Cancer

Current strategies for the design of PROTAC linkers: a critical review

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

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