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 Bclx 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 Bclx 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.

Azobenzene Photoswitches in Proteolysis Targeting Chimeras: Photochemical Control Strategies and Therapeutic Benefits

“…[40] Also, the route of administration can play a vital role in enhancing the degradation efficiency, as was observed with other types of PROTACs when administered through intravenous and intraperitoneal injections. [40] The UV light used in these experiments has low tissue penetration and restricts light-controlled PROTACs to topical use, such as leukemia and skin cancers. Therefore, investigating other photoswitches and light sources will mitigate these issues.…”

“…However, selecting appropriate intermembrane transporters [37] or specific‐cell receptors (such as FOLR1 and HER2) for the guided delivery can address these issues [38,39] . Additionally, their conjugations with coenzymes (such as folic acid, pyridoxine) and antibodies could improve their cell selectivity and uptake [40] . Also, the route of administration can play a vital role in enhancing the degradation efficiency, as was observed with other types of PROTACs when administered through intravenous and intraperitoneal injections [40] .…”

“…Additionally, their conjugations with coenzymes (such as folic acid, pyridoxine) and antibodies could improve their cell selectivity and uptake [40] . Also, the route of administration can play a vital role in enhancing the degradation efficiency, as was observed with other types of PROTACs when administered through intravenous and intraperitoneal injections [40] . The UV light used in these experiments has low tissue penetration and restricts light‐controlled PROTACs to topical use, such as leukemia and skin cancers.…”

From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs

“…12: 220171 encapsulation [77]. In the future, inhibitor of apoptosis (IAP)-based PROTACs could also hold promise as senolytics [78], especially in the light of recent work reporting on the overexpression of some IAP members in senescence [62].…”

Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

“…Currently, structural optimization of PROTACs mainly focuses on the evaluation of the structure–activity relationship (SAR) for various size linkers [ 55 ]. Previous studies have also demonstrated that the linker’s length does not influence the target binding affinity but can instead have a major impact on cytotoxicity since longer linkers have been shown to be more toxic [ 60 ]. Conversely, PROTACs with longer linkers show increased efficiency in mediating target protein degradation during the ubiquitination process.…”