Development of the first small molecule histone deacetylase 6 (HDAC6) degraders

Yang, Kuo‐Ho; Song, Yanling; Xie, Haibo; Wu, Hao; Wu, Yi-Ting; Leisten, Eric D; Tang, Weiping

doi:10.1016/j.bmcl.2018.05.057

Cited by 152 publications

(146 citation statements)

References 63 publications

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“…73 The designed PROTAC against ALL also promoted the degradation of other kinase such as PTK2, Aurora A, FER, and RPS6KA1. 80 To date, PROTACs targeting RAR, 54 PI3K, 82 CRABPI/II, 53,55 ALK4, 83 Smad3, 84 CDK9, 50,85 HDAC6, 86 Sirt2, 87 BTK, 88-90 CK2 casein kinase 2, 91 and TBK1 92 are also reported. 93 Most of the proteins are cellular located or nuclear located.…”

Section: Targeting Protein Kinasesmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

201

135

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Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. Significance of the study This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

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Section: Targeting Protein Kinasesmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

201

135

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“…In 2014, the crystal structures of DDB1-CRBN complexes bound to thalidomide [14] and lenalidomide [15] were solved. Since then, PROTACs with IMiD small molecules targeting CRBN and diverse proteins of interest, including the bromodomain and extra-Terminal (BET) proteins (BRD2/3/4) [16][17][18], FKBP12 [16], BCR-ABL [19], BRD9 [20], Sirt2 [21], CDK9 [22,23], FLT3 [24], BTK [24,25], ALK [26], CDK4/CDK6 [27,28] and HDAC6 [29] have been reported.…”

Section: Cereblon (Crbn)-based Degradersmentioning

confidence: 99%

“…A library of 25 hetero-bifunctional molecules with various linker sizes and attachment chemistry was synthesized. The lead PROTAC QC-01-175 (29) was evaluated in a biolayer interferometry (BLI) assay for degradation against the wild-type and the two variant forms of recombinant human tau: A152T and P301L. Although the PET tracer 18 F-T807 shows off-target activity against the monoamine oxidases A and B (MAO-A, MAO-B), the off-target MAO binding was significantly reduced with the PROTAC QC-01-175.…”

Section: Tau-protacsmentioning

confidence: 99%

PROTACs– a game-changing technology

Konstantinidou

Zhang

et al. 2019

Expert Opinion on Drug Discovery

127

109

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Introduction: Proteolysistargeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

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“…This research indicates that PROTAC technology could be counted as a promising therapy for drug-resistant cancers. In addition to the above, CRBN-based PROTACs showed efficiencies against CDK9, 27,28 BTK, 29 HDAC6, 30 ALK, 31 BCR-ABL, 32 Sirt2 (ref. 33) and PI3K 34 that were better than the original inhibitors.…”

Section: Mdm2-based Protacmentioning

confidence: 91%