Small molecule-based immunomodulators for cancer therapy

Abstract

Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to pharmacodynamics (e.g., specificity and efficacy). However, they have limitations in terms of pharmacokinetics including long half-lives, poor tissue/tumor penetration, and little/no oral bioavailability. In addition, therapeutic antibodies are immunogenic, thus may cause unwanted adverse effects. Therefore, researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy, as small molecules may overcome the above disadvantages associated with antibodies. Further, small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment, and may be combined to elicit synergistic effects. Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy. In this review, we describe the current progress in small molecule-based immunomodulators (inhibitors/agonists/degraders) for cancer therapy, including those targeting PD-1/PD-L1, chemokine receptors, stimulator of interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.

Keywords: Agonists; Cancer immunotherapy; Immunomodulators; Inhibitors; Small molecules.

Graphical abstract

Figure 1

Overview of immune targets related to innate immune system, adaptive immune system, and tumor microenvironment (TME).

Figure 2

(A) PD-1/PD-L1 interaction between T cell and tumor cells. (B) Pharmacophore model of PD-1/PD-L1 immunomodulators. (C) Chemical structures of representative small molecule PD-1/PD-L1 modulators.

Figure 3

(A) RORγt signaling pathways in tumor immunity. RORγt agonists act by integrating into a single treatment several antitumor mechanisms, which can disrupt the interactions between PD-1 and PD-L1, increase the production of IL-17A, and reduce Treg formation to achieve anti-tumor effects. (B) Chemical structures of representative RORγt agonists. (C) The multifaceted roles of chemokines and their receptors in tumorigenesis. Chemokines are found in tumor cells, intratumor stromal cells, while chemokine receptors are mainly expressed on the surface of tumor cells as well as immune cells including MDSC, CD8⁺T, NK, and Treg. Chemokine ligands can bind to their corresponding chemokine receptors, resulting in different immune responses (e.g., inducing cancer cell proliferation or promoting anti-tumor effects). MDSC, myeloid-derived suppressor cell; NK, natural killer cell; TAM, tumor-associated macrophage; Treg, regulatory T cell; chemokine: CXCL1, CXCL10, CXCL12, CCL2, CCL5, CXL22; chemokine receptor: CXCR2, CXCR4, CCR2, CCR3, CXCR4, CXCR5. (D) Chemical structures of representative chemokine receptor antagonists.

Figure 4

(A) The tumor promoting effects of TGF-β signaling. Firstly, TGF-β could enhance immune evasion by decreasing the activation of T cell, APC cells and NK cells; next, TGF-β promotes the proliferation of tumor cells through stimulation of angiogenesis as well as metastasis. Lastly, as a major EMT (epithelial mesenchymal transition) regulator, TGF-β plays a crucial role in the development of tumors. (B) Chemical structures of representative TGF-β inhibitors. (C) SHIP1 signaling in haematolymphoid cells. (D) Chemical structure of a representative SHIP1 inhibitor.

Figure 5

(A) Overview of the Sting signaling pathway. (B) Chemical structures of representative STING agonists.

Figure 6

(A) The roles of TLRs in antitumor immunity. Agonizing specific TLRs (e.g., TLR3, 5, 9, and TLR7/TLR8) can trigger antitumor immunity through the activation of CTL, DC, NK and inhibition of Treg. (B) Chemical structures of representative TLR agonists.

Figure 7

(A) The role of IDO in T cell anergy and immune tolerance. The activation of IDO causes the degradation of tryptophan (Trp) into kynurenine (Kyn), resulting in T cell anergy via the activation of GCN2 and inhibition of mTOR, and the acceleration of Treg differentiation. (B) Chemical structures of representative IDO-based dual inhibitors.

Figure 8

(A) Role of arginase in immunosuppression. Arginase is able to catalyze the conversion of l-arginine into l-ornithine and urea. Depletion of l-arginine prevents the activation of cytotoxic T cells and NK cells in tumors, thus causing immunosuppression. (B) Chemical structures of representative arginase inhibitors. (C) Mechanism of adenosine-mediated tumor survival and immunosuppression. CD39 and CD73 catabolize the production of adenosine from ATP. Adenosine can promote the proliferation of tumor cells and prevent the activation of T cells, NK cells, DC in tumors, resulting in immunosuppression. (D) Chemical structures of representative A2A adenosine receptor antagonists.

Figure 9

(A) Mechanism of AhR pathway in immunosuppression. (B) Chemical structures of representative AhR inhibitors. (C) Phosphoinositide 3-kinase (PI3K)-δ pathway in the regulation of Tregs and anti-cancer immunity. (D) Chemical structures of representative PI3K-δ inhibitors. (E) Chemical structures of representative BTK inhibitors.