Targeting the Immune System in Cancer with Small Molecules

Small Molecules for Immuno-oncology

Recent clinical successes in targeting the immune system for the treatment of cancer have harnessed biologicals, including antibodies, proteins, engineered cells and oncolytic viruses. Small molecules directed at the immune system offer advantages over biologicals; they can target intracellular targets that protein based therapeutic agents can’t access; they have high oral bioavailability; and they reach high levels in the local tumor microenvironment. Additionally, small molecules can regulate immunosuppressive cell types, such as tumor associated macrophages (TAMs) and dendritic cells, that are not directly regulated by immune checkpoint blockers.

Table 1: A selection of cancer immunology products available from Tocris

Cat. No. Product Name Action Description



TLR7 agonist

TRL7 activation induces release of proinflammatory cytokines and activation of NF-κB signaling. Imiquimod activates antigen presenting cells and antitumor cellular immune response.



IDO inhibitor

IDO activity in tumors inhibits proliferation and induces apoptosis of T-cells. Inhibition with 1-Methyl-D-tryptophan enhances the antitumor immune response of T-cells in vitro.


LM 10

TDO inhibitor

TDO is expressed in tumors and prevents immune rejection of tumor cells. Inhibition with LM 10 restores ability of mice to reject TDO expressing tumors.


AZ 10397767

CXCR2 antagonist


CXCR2 ligands recruit neutrophils to tumors. Antagonism with AZ 10397767 reduces recruitment both in vitro and in vivo and is associated with slower growing tumors.


2’,3’-cGAMP sodium salt

STING agonist


2’,3’-cGAMP binds to stimulator of interferon genes (STING) to activate the innate immune response. Causes repolarization of TAMs to antitumor phenotype.


INCB 024360-analog

IDO inhibitor


Inhibition of IDO with INCB 024360-analog enhances antitumor immune response and inhibits tumor growth in vivo.


PSB 12379

Ecto-5'-nucleotidase (CD73) inhibitor


CD73 catalyzes hydrolysis of extracellular AMP to adenosine, which causes local immunosuppression via adenosine receptors. Inhibition with PSB 12379 causes immune response in tumor microenvironment.


Immune cell signaling is a mechanism that can be easily modulated with small molecules and a number of different pathways show promise as targets. Toll-like receptors are expressed on antigen presenting cells as part of the innate immune system, and trigger a pro-inflammatory response upon ligand binding. Agonists for TLR7 and TLR8 have shown promise in pre-clinical results (Adams et al, 2015) and subsequently the TLR7 agonist Imiquimod (Cat. No. 3700) has been approved as a topical monotherapy for basal cell carcinoma (Geisse et al, 2004). These small molecules have antitumor effects mediated by the activation of dendritic cells and natural killer cells to kill tumor cells, and the suppression of T-cells (Pradere et al, 2014).

A further target in the innate immune system is stimulator of interferon genes (STING), a pattern recognition receptor and adapter protein that mediates a TLR independent immune response to the detection of cytoplasmic DNA. Activation of STING, by cyclic dinucleotide following breakdown of foreign DNA, triggers a cascade resulting in the transcription of pro-inflammatory immune system genes. STING agonists, including 2’,3’-cGAMP (Cat. No. 5945) are cyclic nucleotides and aim to activate an immune response in the tumor microenvironment. Intra-tumoral injection of the STING agonist ADU-S100 is currently under investigation in phase 1 clinical trials (Toogood, 2018).

Chemokines and their receptors play a critical role in the immune response in cancer, and as G-protein coupled receptors, chemokine CXC receptors are a druggable target for oncotherapy. AMD 3100 (Cat. No. 3299) is a CXCR4 antagonist and in pre-clinical investigations it switches the inflammatory response from a Th2 to Th1 type response so promoting a pro-inflammatory environment (Hogaboam et al, 2005). Also (±)-AMG 487 (Cat. No. 4487) has been shown to inhibit lung metastasis in a mouse model of metastatic breast cancer (Walser et al, 2006).

Amino acid metabolism is a conserved pathway that is involved in the regulation of the immune response. The IDO family of dioxygenases (IDO1, IDO2 and TDO), responsible for the conversion of tryptophan to kynurenine and additional metabolites, have shown promise as therapeutic targets in cancer. Multiple immunosuppressive roles have been shown for IDO, which ultimately impair immune recognition and promote tumor growth. Inhibition of IDO/TDO was one of the first small molecule based strategies proposed for the induction of the immune response in cancer (Mellor & Dunn, 2004). In pre-clinical investigations 1-Methyl-D-tryptophan (Cat. No. 5698), an IDO inhibitor, enhanced the antitumor and antiviral immunoresponse of CD8 positive T-cells in vitro (Rytelewski et al, 2014), and also reduced tumor volume in mice with xenografts overexpressing IDO (Nakamura et al, 2015). This small molecule, also known as Indoximod, is currently being studied in 5 clinical trials (Toogood, 2018)

Several comprehensive reviews, further discussing the targeting of immune response pathways with small molecules for cancer treatment, have recently been released. These reviews, listed below, outline the rationale for small molecule use and provide an update on those currently undergoing clinical trials.


Adams et al. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 14, 603. PMID: 26228631

Dhanak et al. (2017) Small-molecule targets in immuno-oncology. Cell Chem Biol. 24, 1148. PMID: 28938090

Geisse et al . (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 50, 722. PMID: 15097956

Hogaboam et al. (2005) The therapeutic potential in targeting CCR5 and CXCR4 receptors in infectious and allergic pulmonary disease. Pharmacol Ther. 107, 314. PMID: 16009428

Kamta et al. (2017) Advancing cancer therapy with present and emerging immuno-oncology approaches. Front Oncol. eCollection 2017. PMID: 28459041

Mellor & Dunn (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 4, 762. PMID: 15459668

Nakamura et al. (2015) Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. Int J Hematol. 102, 327. PMID: 26243621

Pradere et al. (2014) The yin and yang of Toll-like receptors in cancer. Oncogene. 33, 3485. PMID: 23934186

Rytelewski et al. (2014) Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase. PLoS One 9, e90439. PMID: 24587363

Toogood (2018) Small molecule immuno-oncology therapeutic agents. Bioord Med Chem Letts. 28, 319. PMID: 29326017

Walser et al. (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res. 66, 7701. PMID: 16885372