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

in Chembiochem : a European journal of chemical biology by Arvind Negi, Anne Sophie Voisin-Chiret

TLDR

  • The study is about finding ways to stop cancer cells from growing. The researchers looked at a protein called Bcl-x, which helps cancer cells survive. They found that a drug called ABT-263 can stop Bcl-x from working, but it also hurts human platelets, which are a type of blood cell. The researchers then looked at other drugs that can stop Bcl-x from working, and they found that some of these drugs work better than ABT-263. They also found that some drugs work better than others because they are designed to work differently. The researchers suggest that these drugs could be used to treat cancer and other diseases.

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

Overview

  • The study focuses on apoptosis, a highly regulated cellular process, and its aberration in various disorders. Bcl-x, an antiapoptotic protein, is a promising anticancer and senolytic target due to its common expression in solid tumors and some leukemias and lymphomas. The study aims to compare the outcomes observed under different experimental conditions or interventions and discuss the key findings of the study and their implications for the initial hypothesis. The methodology used for the experiment includes the subject demographics and specific procedures or tests conducted. The primary objective of the study is to identify potential Bcl-x inhibitors and evaluate their therapeutic index in platelets.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, including classical Bcl-x inhibitor designs and event-driven pharmacology-based approaches such as proteolysis targeting chimeras (PROTACs) and SNIPERs. The study identifies significant differences in the results between these conditions, with event-driven pharmacology-based approaches showing a significant improvement in platelet therapeutic index than their parent molecules. The key findings of the study highlight the potential of PROTACs as Bcl-x inhibitors due to their distinctive pharmacology and molecular size, which improves their cell selectivity. The study also discusses prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal), and their potential as Bcl-x inhibitors.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they identify potential Bcl-x inhibitors and evaluate their therapeutic index in platelets. The study also highlights the potential of event-driven pharmacology-based approaches, such as PROTACs, as Bcl-x inhibitors. The study suggests future research directions, including the development of Bcl-x-based PROTACs and prodrug-based approaches, to further explore their potential as anticancer and senolytic targets. The study also identifies limitations, such as the need for further preclinical and clinical studies to evaluate the safety and efficacy of these inhibitors.
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