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Review
. 2022 Nov 17:12:992171.
doi: 10.3389/fonc.2022.992171. eCollection 2022.

Utilization of macrocyclic peptides to target protein-protein interactions in cancer

Jiawen Yang  1   2   3 , Qiaoliang Zhu  1 , Yifan Wu  2   4   5 , Xiaojuan Qu  2   4   5 , Haixia Liu  2   5   6 , Biao Jiang  2   6 , Di Ge  1 , Xiaoling Song  2
Affiliations
Review

Utilization of macrocyclic peptides to target protein-protein interactions in cancer

Jiawen Yang et al. Front Oncol. .

Abstract

Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.

Keywords: cancer; drug; macrocyclic peptide; protein-protein interactions; treatment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Macrocyclic peptides targeting extracellular protein-protein interactions. This scheme shows macrocyclic peptides-targeted extracellular proteins, the related signaling pathways, and their cellular functions. (A) somatostatin analogs. Lanreotide and pasireotide are somatostatin analogs. They can inhibit the activation of somatostatin receptors by endogenous somatostatin to inhibit cell proliferation. (B) C-X-C chemokine receptor (CXCR4) antagonists. Motixafortide, balixfortide, LY2510924, and Pep R54 can inhibit the interaction between CXCR4 and CXCL12, which is essential for cancer cell proliferation. (C) Inhibitory immune checkpoint inhibitors. BMSpep-57,77,99, BMS-986189, and C8 can inhibit the interaction between programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which negatively modulate the adaptive immune systems. D4-2 can inhibit the interaction between CD47 and signal-regulatory protein (SIRP)α, which releases an inhibitory ‘do not eat me’ signal to lead to cancer cell evasion of immune detection and clearance. The PD-1/PD-L1 axis and CD47/SIRPα axis are critical for cancer immunotherapy. (D) Hedgehog (HH) signaling protein inhibitors. HL2-m5 can inhibit the activation of the HH pathway, which regulates target gene expression. (E) Receptor tyrosine kinase (RTK) inhibitors. HiP-8 can inhibit the hepatocyte growth factor (HGF)-mesenchymal-epithelial transition tyrosine kinase receptor (MET) interaction which is critical for cancer cell proliferation, migration, and invasion.
Figure 2
Figure 2
Macrocyclic peptides targeting somatostatin receptors. (A) Lanrenotide. IC50: 57 nM in GH cells; (B) Pasireotide, IC50: 0.4±0.1 nM in rat pituitary cells.
Figure 3
Figure 3
Macrocyclic peptides targeting CXC chemokine receptor 4 (CXCR4). (A) Motixafortide, IC50: 1 nM; (B) Balixafortide, IC50: 10 nM; (C) LY2510924, IC50: 0.0797 nM in CCRF-CEM cells; (D) Peptide R54, IC50: 1.5 nM in CCRF-CEM cells.
Figure 4
Figure 4
Macrocyclic peptides targeting immune checkpoints. (A) BMSpep-57, IC50=9nM and EC50 =566±122 nM in Jurkat cells; (B) BMSpep-71, IC50= 7nM and EC50 =293±93 nM in Jurkat cells; (C) BMSpep-99, IC50=153 nM and EC50 =6.3±3.28 µM in Jurkat cell; (D) C8, Kd=0.64±0.19 µM; (E) D4-2, IC50 = 0.18 µM
Figure 5
Figure 5
Macrocyclic peptides targeting Hedgehog (HH) signaling protein and receptor tyrosine kinases. (A) HL2-m5, Kdh170±20nM and IC50=290 nM; (B) HIP-8, Kd=0.93 nM and IC50=0.9 nM.
Figure 6
Figure 6
Macrocyclic peptides targeting intracellular protein-protein interactions. This schematic shows the cell uptake mechanisms of macrocyclic peptides, intracellular proteins, related signaling pathways, and cellular functions. (A) Overview of cell uptake mechanisms of macrocyclic peptides. Some macrocyclic peptides can cross the cell membrane in a passive way as small-molecule drugs. Other macrocyclic peptides may cross the cell membrane via receptor-mediated endocytosis, pinocytosis and pinosomal escape, and active transportation. (B) Macrocyclic peptides can target microtubule-associate protein light chain (LC)3 which is essential for the maturation of the autophagosome. (C) Macrocyclic peptides can target the ubiquitin-proteasome system which regulates many aspects of cell biology. (D) Macrocyclic peptides can target KRAS mutations which are important for cell survival, proliferation, and cytoskeletal organization.
Figure 7
Figure 7
Macrocyclic peptide targeting autophagy. HL2-m5, Kd= 120 nM for LC3A and 192 nM for LC3B.
Figure 8
Figure 8
Macrocyclic peptides targeting the ubiquitin-proteasome system (UPS). (A) CM11-1, Kd= 0.6 nM; (B) ATSP-7041, Kd= 0.91 nM for MDM2 and 2.3 nM for MDMX; (C) ALRN-6924, IC50=7.7 nM for MDM2 and 24.7 nM for MDMX; (D) hD1, Ki= 180 nM and IC50=100 nM; (E) Ub4a, Kd= 9±3 nM; (F) mJ08-L8W, Kd= 1.2 nM.
Figure 9
Figure 9
Macrocyclic peptides targeting KRAS. (A) KS-58, EC50= 22 nM; (B) MP-3995, IC50= 0.5 nM.
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