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

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 is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-x is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-x is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-x is a promising anticancer and senolytic target. Various nanomolar range Bcl-x inhibitors 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-x protein in the survival of human platelets. Classical Bcl-x 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 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 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.