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Strategies to Reduce the On-Target Platelet Toxicity of Bcl-x_L Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches.

ABSTRACT: 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-x_L is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-x_L is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-x_L is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-x_L is a promising anticancer and senolytic target. Various nanomolar range Bcl-x_L inhibitors have been developed. ABT-263 was successfully identified as a Bcl-x_L /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-x_L protein in the survival of human platelets. Classical Bcl-x_L 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-x_L 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-x_L 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.

SUBMITTER: Negi A

PROVIDER: S-EPMC9311450 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches.

Negi Arvind A Voisin-Chiret Anne Sophie AS

Chembiochem : a European journal of chemical biology 20220319 12

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 c ...[more]

PMID: 35263486

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Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.

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Strategies to Reduce the On-Target Platelet Toxicity of Bcl-x_L Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches.

Publications

Strategies to Reduce the On-Target Platelet Toxicity of Bcl-x<sub>L</sub> Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches.

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