Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐x(L) 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(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.