Small molecule drugs with immunomodulatory effects in cancer

Murphy, Adrian; Li, Zheng

doi:10.1080/21645515.2015.1057363

Cited by 32 publications

(21 citation statements)

References 50 publications

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“…Overall, small molecule immunomodulators offer greater flexibility than the monoclonal antibodies and have the potential to augment the therapeutic benefits of existing cytotoxic, targeted, and immunotherapeutic agents. Numerous small molecules with immunomodulatory effects are currently being pursued, including indoleamine‐2,3‐dioxygenase (IDO) inhibitors, toll‐like receptor agonists, and RAR‐related orphan receptor gamma T (RORγt) inhibitors . Most notably, preclinical studies of IDO inhibitors have shown that these small molecule immunomodulators can empower the efficacy of cytotoxic chemotherapy, radiotherapy, and immune checkpoint therapy without additional toxicity .…”

Section: Discussionmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

145

121

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Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

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Section: Discussionmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

145

121

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“…For example, MEK inhibitors target the RAS-RAF-MEK1/2-ERK1/2 pathway, which is constitutively activated by KRAS mutations and renowned for its role in cellular proliferation and tumorigenesis, but MEK inhibitors have also been shown to increase T-cell infiltration and reduce MDSCs in the TME [68]. Other small molecule inhibitors, such as inhibitors of indoleamine-2,3-dioxygenase (IDO), have also been shown to affect a myriad of immune cell types [20,69,70]. These small molecules can overcome traditional checkpoint inhibitor resistance through non-redundant immune pathway mechanisms and are thus viable options for combination therapy with checkpoint inhibition.…”

Section: Advantages Of Immunomodulatory Small Molecule Inhibitorsmentioning

confidence: 99%

Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape

Osipov

Saung

et al. 2019

j. immunotherapy cancer

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175

131

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Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.

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“…IDO1 is encoded by the IDO1 gene and is an intracellular enzyme that is involved in the rate-limiting step of the catabolism of L-tryptophan, an important regulator of metabolism. Tryptophan starvation and the influx of downstream catabolites such as kynurenine suppress the activation of T cells and NK cells while enhancing Treg differentiation and immunosuppression (9)(10)(11). Tumor cells transfected with IDO1 were not rejected in mice treated with a vaccine therapy (12).…”

Section: Introductionmentioning

confidence: 99%

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

Blair

Kleponis

Thomas

et al. 2019

Journal of Clinical Investigation

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Small molecule drugs with immunomodulatory effects in cancer

Cited by 32 publications

References 50 publications

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

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