Small-Molecule PROTACs for Cancer Immunotherapy

Abstract

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

In-situ formed thermosensitive hydrogel amplifies statin-mediated immune checkpoint blockade for coordinated tumor chemo-immunotherapy

“…The expression level of PD-L1 on CT26 cell surface upon ATO treatment was about 40% of untreated group ( Figure 2A ), indicating that ATO suppressed PD-L1 expression on colon cancers. It should be noted that CTX upregulated PD-L1 on CT26 cells ( Figure 2A ), which was in line with other chemotherapeutic drugs ( Liu et al, 2022a ; Liu et al, 2022b ). Compared with single treatment of CTX, treatment of CTX + ATO had a lower PD-L1 expression ( Figure 2A ), indicating that chemotherapy-induced PD-L1 upregulation could be reversed by statins.…”

“…Although many small molecule drugs and their combination with immune checkpoint blockade antibodies have proved clinical efficacy against solid tumors, one of the major limitations of these therapies is their rapid diffusion from the target tissue ( Zhuang et al, 2019 ; Liu et al, 2022a ; Liu et al, 2022b ). The incorporation of ICD-inducing chemotherapeutics and PD-L1-inhibiting drugs into a hydrogel drug delivery system is sufficient to overcome this difficulty and realize satisfactory tumor inhibition.…”

Design of Tracers in Fluorescence Polarization Assay for Extensive Application in Small Molecule Drug Discovery

“…With a molecular weight of less than approximately 900 Da, small molecules can quickly cross the cell membrane to reach the site where action is needed . At the same time, due to their advantages in manufacturing, storage, transportation, and cost, they also have many applicable situations. , In addition, according to a series of research studies, small molecules with specific binding sites have good characteristics in inhibiting a specific function of a multifunctional protein and interfering PPI …”

“…With a molecular weight of less than approximately 900 Da, small molecules can quickly cross the cell membrane to reach the site where action is needed. 97 At the same time, due to their advantages in manufacturing, storage, transportation, and cost, they also have many applicable 98,99 In addition, according to a series of research studies, small molecules with specific binding sites have good characteristics in inhibiting a specific function of a multifunctional protein and interfering PPI. 100 Based on its superior properties, much research focuses on the design of FP tracers using small molecules as ligands and thereby facilitates the use of FP to screen extended small molecule drugs.…”

Cancer-Specific Delivery of Proteolysis-Targeting Chimeras (PROTACs) and Their Application to Cancer Immunotherapy

“…TMEs restrict the invasion of effective immune cells and hinder their antitumor immunity, whereas oncogenic proteins are directly or indirectly related to establishing those circumstances [ 21 ]. Thus, the PROTAC-mediated degradation of oncogenic proteins facilitates the antitumor immune activation through the straightforward disruption of the immune checkpoint system or elimination of immunomodulatory signaling in tumor tissues [ 22 ]. In addition, the depletion of certain proteins by PROTAC treatment can induce cancer cell apoptosis that discharges damage-associated molecular patterns (DAMPs), which is called immunogenic cell death (ICD) [ 23 ].…”