Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

Robb, Caroline M.; Contreras, Jacob I.; Kour, Smit; Taylor, Margaret; Abid, Mohammad; Sonawane, Yogesh A.; Zahid, Muhammad; Murry, Daryl J.; Natarajan, Amarnath; Rana, Sandeep

doi:10.1039/c7cc03879h

Cited by 178 publications

(144 citation statements)

References 44 publications

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“…This PROTAC is composed of a short peptide that binds to E3 ubiquitin ligase and a small molecular that binds to target protein, respectively, followed by polyubiquitination and proteasome degradation of target FIGURE 4 A schematic diagram of the small molecule-based PROTACs. 50 To date, small molecule-based PROTACs have been generated to recruit MDM2, cellular inhibitor of apoptosis protein 1 (cIAP1), CRBN (cereblon), and, of course, VHL (for review, see Toure and Crews 51 ). 43 Furthermore, this hydroxyproline derivatives were further used for the synthesis of HaloPROTACs to target HaloTag7 fusion proteins, by developing chloroalkane-containing PROTACs against Halo Tag7 fusion protein using the acyl amine moiety for recognizing VHL.…”

Section: Small Molecule-based Protacmentioning

confidence: 99%

“…49 For targeting kinases, a PROTAC against CDK9 was designed by using CDK9 inhibitor and thalidomide for targeting cereblon. 50 To date, small molecule-based PROTACs have been generated to recruit MDM2, cellular inhibitor of apoptosis protein 1 (cIAP1), CRBN (cereblon), and, of course, VHL (for review, see Toure and Crews 51 ). 15,52 To overcome the shortage of insufficient membrane permeability and stability of the peptide-based PROTACs, Hashimoto group focused on using cIAP1, which promotes ubiquitination and proteasomal degradation of interacting proteins.…”

Section: Small Molecule-based Protacmentioning

confidence: 99%

“…The authors examined this PROTAC in HCT116 cells and observed that it selectively degrades CDK9 without affecting other CDK family members. 50 More PROTACs on CDK9 were developed by using a natural product Wogonin, which is similar to CDK9 inhibitor Flavopiridol. 78 In 2018, Zhang reported their design of a PROTAC against ALK by using ALK inhibitors.…”

Section: Targeting Protein Kinasesmentioning

confidence: 99%

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The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

186

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: Small Molecule-based Protacmentioning

confidence: 99%

Section: Small Molecule-based Protacmentioning

confidence: 99%

Section: Targeting Protein Kinasesmentioning

confidence: 99%

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The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

186

135

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“…Therefore, thalidomide‐based PROTACs have been identified as protein degradation inducers for bromodomain proteins (see section 3.1) and kinases, such as abelson tyrosine kinase (ABL), CDK8, CDK9, ERK1/2 and (Figure B) . Compound 12 (Figure B) is a PROTAC that selectively degrades CDK9 and compound 13 (Figure B) is a PROTAC based on in‐cell click‐formed proteolysis‐targeting chimeras (CLIPTACs, see section 3.1) . Compound 14 reported by Crews’ group was designed based on dasatinib as a kinase binder and 11 a as a CRBN binder (Figure B) .…”

Section: Chemical Protein Degradation Approachmentioning

confidence: 99%

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Itoh

2018

The Chemical Record

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In addition to traditional drugs, such as enzyme inhibitors, receptor agonists/antagonists, and protein-protein interaction inhibitors as well as genetic technology, such as RNA interference and the CRISPR/Cas9 system, protein knockdown approaches using proteolysis-targeting chimeras (PROTACs) have attracted much attention. PROTACs, which induce selective degradation of their target protein via the ubiquitin-proteasome system, are useful for the down-regulation of various proteins, including disease-related proteins and epigenetic proteins. Recent reports have shown that chemical protein knockdown is possible not only in cells, but also in vivo and this approach is expected to be used as the therapeutic strategy for several diseases. Thus, this approach may be a significant technique to complement traditional drugs and genetic ablation and will be more widely used for drug discovery and chemical biology studies in the future. In this personal account, a history of chemical protein knockdown is introduced, and its features, recent progress in the epigenetics field, and future outlooks are discussed.

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“…Over the past decade, PROTACs have been developed to address an ever-expanding collection of target proteins. Owing to the availability of well-validated chemical matter to repurpose as PROTAC warheads, the majority of early reports focused on degraders of hormone receptors [10][11][12][13], BET-family proteins [14][15][16] and kinases [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. More recently, the applicability of PROTACs has been broadened to include multi-functional proteins (e.g., TRIM24 [34], SMARCA2 [35] tau [36,37]), and HaloTag7-fused proteins for chemical genetics [38].…”

Section: Introductionmentioning

confidence: 99%

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

Bai

Kirubakaran

Karanicolas

2020

Preprint

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PROTACs are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components, then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined.We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation, and that members of a structurally-conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes. Significance StatementRecent years have brought a flood of interest in developing compounds that selectively degrade protein targets in cells, as exemplified by PROTACs. Fully realizing the promise of PROTACs to transform chemical biology by delivering degraders of diverse and undruggable protein targets has been impeded, however, by the fact that designing a suitable chemical linker between the functional moieties requires extensive trial and error. Here, we describe a structure-based computational method to predict PROTAC activity. We envision that this approach will allow design and optimization of PROTACs for efficient target degradation, selection of E3 ligases best suited for pairing with a given target protein, and understanding the basis by which PROTACs can exhibit different target selectivity than their component warheads.

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Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

Cited by 178 publications

References 44 publications

The PROTAC technology in drug development

The PROTAC technology in drug development

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

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