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

ABSTRACT: BCL-X_L is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-X_L 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-X_L is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-X_L inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-X_L for survival. In this review, we discuss how BCL-X_L-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-X_L inhibition. We summarize the progress in the development of BCL-X_L 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-X_L PROTACs can significantly improve the therapeutic window compared to conventional BCL-X_L 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.

SUBMITTER: Zhang P

PROVIDER: S-EPMC8293695 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhang Peiyi P Zhang Xuan X Liu Xingui X Khan Sajid S Zhou Daohong D Zheng Guangrong G

Exploration of targeted anti-tumor therapy 20200831

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 trea ...[more]

PMID: 34296214

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Project description:Apoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-xL is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-xL is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-xL is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-xL is a promising anticancer and senolytic target. Various nanomolar range Bcl-xL inhibitors have been developed. ABT-263 was successfully identified as a Bcl-xL /Bcl-2 dual inhibitor. But it failed in the clinical trial (phase-II) because of its on-target platelet toxicity, which also implies an essential role of Bcl-xL protein in the survival of human platelets. Classical Bcl-xL inhibitor designs utilize occupancy-driven pharmacology with typical shortcomings (such as dose-dependent off-target and on-target platelet toxicities). Hence, event-driven pharmacology-based approaches, such as proteolysis targeting chimeras (PROTACs) and SNIPERs (specific non-genetic IAP-based protein erasers) have been developed. The development of Bcl-xL based PROTACs was expected, as 600 E3-ligases are available in humans, while some (such as cereblon (CRBN), von Hippel-Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand-based Bcl-xL PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (ABT-263: DT2216, PZ703b, 753b, XZ739, PZ15227; A1155463: XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal). Studies of in-vitro, in-vivo, structure-activity relationships, biophysical characterization, and status of preclinical/clinical inhibitors derived from these strategies are also discussed in the review.

Dataset Information

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

Publications

PROTACs are effective in addressing the platelet toxicity associated with BCL-X<sub>L</sub> inhibitors.

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