Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity

Zhang, Xuan; Thummuri, Dinesh; Liu, Xingui; Hu, Wanyi; Zhang, Peiyi; Khan, Sajid; Yuan, Yaxia; Zhou, Daohong; Zheng, Guangrong

doi:10.1016/j.ejmech.2020.112186

Cited by 69 publications

(54 citation statements)

References 48 publications

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“…They first generated a library of degraders conjugating JQ1 (58) to thalidomide (9), and solved the crystal structures of their TC with the thalidomide binding domain of CRL4 CRBN and BRD4 BD1 . Degraders with linkers of a similar length to representative PROTAC dBET23 (103) induced comparable TC architectures, but PROTACs with shorter linkers, such as dBET57 (104) produced TCs involving distinct PPI surfaces ( Figure 22). This was not completely unexpected, since dBET57 contains a two carbon linker, while a minimum of approximately eight carbons would be required to bridge the distance between the E3 and POI binding sites in the dBET23 crystal structure (PDB 6BN7), and is also conjugated from a different position on the warhead.…”

Section: Methodsmentioning

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: Methodsmentioning

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

View full text Add to dashboard Cite

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“…Proteomics studies also showed that DT2216 specifically reduced BCL-X L protein levels [21]. The selective degradation for BCL-X L over BCL-2 was also observed with DT2216 analogs in which the VHL-recruiting moiety of DT2216 was replaced by a celebron (CRBN)recruiting moiety [55,56] or inhibitors of apoptosis protein (IAP)-recruiting moiety [57]. It was observed that DT2216 could form stable BCL-2-DT2216-VHL ternary complexes in vitro using AlphaLISA assay [58] but not in live cells, as determined by nanoBRET assay [59].…”

Section: Bcl-x L -Targeting Protacsmentioning

confidence: 84%

“…Subsequent western blot assays also suggest that the protein levels of selected E3 ligases along with ubiquitin-activating enzyme (E1) and E2 enzymes are also low in human platelets compared to different tumor and senescent cells [21]. Thus, based on these initial observations, several series of BCL-X L -targeting PROTACs have been designed and synthesized by our group [20,21,[55][56][57].…”

Section: Bcl-x L -Targeting Protacsmentioning

confidence: 99%

“…Thus, the reduced platelet toxicity of XZ424 is likely attributable to its minimal induction of BCL-X L degradation and lower cell permeability than A-1155463. Subsequent structural modification led to the discovery of XZ739 ( Figure 6), a bioavailable CRBN-recruiting, ABT-263 derived BCL-X L degrader with a DC 50 of 2.5 nM in MOLT-4 cells [55]. XZ739 is the most potent BCL-X L degrader reported and is 20-fold more potent than ABT-263 against MOLT-4 cells.…”

Section: Bcl-x L -Targeting Protacsmentioning

confidence: 99%

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PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors

Zhang

Liu

et al. 2020

Exploration of Targeted Anti-Tumor Therapy

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BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-XL is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-XL inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-XL for survival. In this review, we discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. We summarize the progress in the development of BCL-XL PROTACs. We highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-XL PROTACs can significantly improve the therapeutic window compared to conventional BCL-XL inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity.

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“…In a light-controllable PROTAC, a photo-removable group is attached to the POI ligand or E3 ligand or linker. Upon light irradiation, the photo-removable group is detached from the light-controllable PROTAC converting it to an active PROTAC for the proteasomal degradation of POI [60][61][62][63]. These Bcl-xL degraders showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases in these cells, indicating that an improved therapeutic window can be achieved by converting a non-selective SMI to a tissue/cell-specific degrader.…”

Section: Bcl-2 Family Proteinsmentioning

confidence: 99%

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

Khan

Huo

et al. 2020

J Hematol Oncol

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a substoichiometric manner), ability to target "undruggable" and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/ selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.

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Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity

Cited by 69 publications

References 48 publications

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

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

PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

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