Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X<sub>L</sub>

Zhang, Xuan; Thummuri, Dinesh; He, Yonghan; Liu, Xingui; Zhang, Peiyi; Zhou, Daohong; Zheng, Guangrong

doi:10.1039/c9cc07217a

Cited by 56 publications

(49 citation statements)

References 49 publications

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“…It is well documented that the identification of appropriate vectors from the warhead and anchor is critical to devise a suitable strategy for their conjugation to the linker and access potent degraders [128]. The availability of high-resolution co-crystal structures for warheads bound to the POIs is an invaluable tool and often a prerequisite for PROTAC design and assembly, in particular to identify solvent-exposed exit vectors on the warhead where a linker can be conjugated with minimal effect on POI binding [129][130][131][132]. As an illustrative example, Maniaci et al [133], utilised the co-crystal structure (PDB 5LLI) of VHL in complex with VH298 (87) for the development of "Homo-PROTACs" for the self-induced degradation of VHL.…”

Section: Exploiting X-ray Crystal Structures Of Protein/ligand Binarymentioning

confidence: 99%

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

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

153

137

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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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Section: Exploiting X-ray Crystal Structures Of Protein/ligand Binarymentioning

confidence: 99%

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

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

153

137

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“…Thus, cell/tissue specificity could be achieved by converting an inhibitor to a PROTAC. In proof of concept studies, both Von Hippel-Lindau (VHL) cullin-2 and cereblon (CRBN) cullin-4A RING E3 ligases, which were found to be minimally expressed in human platelets, have been recruited to degrade BCL-X L [13,14]. The preliminary data support the reduction of on-target platelet toxicity for both CRBN-based and VHL-based PROTAC degraders.…”

Section: Ongoing Strategies In Targeting Bcl-x Lmentioning

confidence: 79%

Targeting anti-apoptotic BCL-2 family proteins for cancer treatment

Zhang

Liu

Zhou

et al. 2020

Future Medicinal Chemistry

Self Cite

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“…Although nearly 10 E3 ligases have been exploited in a TPD context, 3,19 only two -VHL and cereblon -have been structurally characterized via X-ray crystallography in an intermediate ternary complex. Furthermore, although to date VHL and cereblon are undoubtedly the two E3 ligases most commonly utilized for TPD, 23 alternatives are highly sought, both because E3 ligase expression levels may vary in different tissue or cellular environments 21 and as a potential means to combat evolved resistance to PROTAC-mediated TPD. 17 Beyond VHL and cereblon, the thirdmost commonly utilized E3 ligases in a TPD context are the inhibitor of apoptosis (IAP) proteins.…”

Section: Case Study 6: Multiple Protacs Against Multiple Targets Witmentioning

confidence: 99%

“…Towards this latter point, Schapira et al 19 have meticulously established a roadmap for expanding the known E3 ligase repertoire, which will also prove advantageous in the pursuit of tissue-specific PROTACs. 20,21 Another fundamental challenge is the long-recognized fact that, while PROTACs are nominally small molecules, they are nonetheless big small molecules, occupying beyond rule-of-five chemical space. 22 Maple et al 23 recently catalogued a number of key physicochemical properties (molecular weight, clogP, rotatable bond count, etc.)…”

Section: Introductionmentioning

confidence: 99%

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies

Drummond¹,

Henry²,

Li³

et al. 2020

Preprint

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Extending upon our previous publication (Drummond and Williams, J. Chem. Inf. Model.2019, 59, 1634), in this work two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different possible PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.

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Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X_L

Abstract: A proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

Cited by 56 publications

References 49 publications

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

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

Targeting anti-apoptotic BCL-2 family proteins for cancer treatment

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies

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Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL

Abstract: A proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

Cited by 56 publications

References 49 publications

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

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

Targeting anti-apoptotic BCL-2 family proteins for cancer treatment

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies

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Product

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Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X_L