Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model

Lee, Kun-Hung; Yen, Wan-Ching; Lin, Wenye; Wang, Pei-Chen; Lai, You-Liang; Su, Yu‐Chieh; Chang, Chunyu; Wu, Cai-Syuan; Huang, Yu‐Chen; Yang, Chi‐Hwa; Chou, Ling-Hui; Yeh, Teng‐Kuang; Chen, Chiung‐Tong; Shih, Chuan; Hsieh, Hsing‐Pang

doi:10.1021/acs.jmedchem.1c01006

Cited by 27 publications

(15 citation statements)

References 60 publications

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“…However, CD115 also acts as a cellular receptor for the cytokine macrophage colony-stimulating factor (MCSF). Activation of CD115 can shift macrophage polarization towards tumor-promoting M2 cells [ 35 , 44 ]. Hence, therapeutic inhibition of the CD115 receptor can re-polarize macrophages towards M1 and is investigated for its potential role in cancer immunotherapy [ 35 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of CD115 can shift macrophage polarization towards tumor-promoting M2 cells [ 35 , 44 ]. Hence, therapeutic inhibition of the CD115 receptor can re-polarize macrophages towards M1 and is investigated for its potential role in cancer immunotherapy [ 35 , 44 ]. The high CD115 expression detected in the current analysis indicates a potential for targeting CD115 for macrophage modulation in oral cancer.…”

Section: Discussionmentioning

confidence: 99%

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Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Weber

Lutz

Olmos

et al. 2022

Cancers

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Background: The involvement of immune cell infiltration and immune regulation in the progression of oral squamous cell carcinoma (OSCC) is shown. Anti-PD-1 therapy is approved for the treatment of advanced OSCC cases, but not all patients respond to immune checkpoint inhibitors. Hence, further targets for therapeutic approaches are needed. The number of identified cellular receptors with immune checkpoint function is constantly increasing. This study aimed to perform a comparative analysis of a large number of immune checkpoints in OSCC in order to identify possible targets for therapeutic application. Materials and Methods: A NanoString mRNA analysis was performed to assess the expression levels of 21 immune regulatory checkpoint molecules in OSCC tissue (n = 98) and healthy oral mucosa (NOM; n = 41). The expression rates were compared between the two groups, and their association with prognostic parameters was determined. Additionally, relevant correlations between the expression levels of different checkpoints were examined. Results: In OSCC tissue, significantly increased expression of CD115, CD163, CD68, CD86, CD96, GITRL, CD28 and PD-L1 was detected. Additionally, a marginally significant increase in CD8 expression was observed. BTLA and PD-1 levels were substantially increased, but the differential expression was not statistically significant. The expression of CD137L was significantly downregulated in OSCC compared to NOM. Correlations between immune checkpoint expression levels were demonstrated, and some occurred specifically in OSCC tissue. Conclusions: The upregulation of inhibitory receptors and ligands and the downregulation of activators could contribute to reduced effector T-cell function and could induce local immunosuppression in OSCC. Increased expression of activating actors of the immune system could be explained by the increased infiltration of myeloid cells and T-cells in OSCC tissue. The analysis contributes to the understanding of immune escape in OSCC and reveals potential targets for oral cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Weber

Lutz

Olmos

et al. 2022

Cancers

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“…Molecular docking was employed to predict the binding free energy between identified compounds with AKT1(PDBID: 4EJN), PI3K(PDBID: 3L54), JNK(PDBID: 3ELJ), PDE3A(PDBID: 7L29), NOS2(PDBID: 4NOS), NOS1(PDBID: 6CIC), SYK(PDBID: 1XBC), STAT1(PDBID: 1BF5), STAT3(PDBID: 1BG1), STAT5(PDBID: 1Y1U), cSRC(PDBID: 2BDF), PPARG(PDBID: 3GZ9), TLR4(PDBID: 3VQ1), MAPK14(PDBID: 1A9U), MTOR(PDBID: 4JT6), ITGAM(PDBID: 1IDO), JAK1(PDBID: 3EYG), JAK2(PDBID: 4D0X), JAK3(PDBID: 3LXK), IKK PDBID: (4KIK), RAC1(PDBID: 5N6O), TYK2(PDBID: 4GIH), CSF1R(PDBID: 3LCO), Tubulin(PDBID: 1SA0), COX2(PDBID: 6COX) according to literature [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. The 2-D structures of the small molecules were retrieved from the PubChem database and converted to 3-D structures by Open Babel.…”

Section: Methodsmentioning

confidence: 99%

Bioinformatics-Guided Identification of Ethyl Acetate Extract of Citri Reticulatae Pericarpium as a Functional Food Ingredient with Anti-Inflammatory Potential

Ma¹,

Jin

Qian

et al. 2022

Molecules

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Citri Reticulatae Pericarpium (CRP) is one of the most commonly used food supplements and folk medicines worldwide, and possesses cardiovascular, digestive, and respiratory protective effects partially through its antioxidant and anti-inflammatory functions. The unique aromatic flavor and mild side effects make CRP a promising candidate for the development of anti-inflammatory functional food. However, recent studies show that the crude alcoholic extract and some isolated compounds of CRP show compromised anti-inflammatory activity, which became the main factor hindering its further development. To identify the bioactive compounds with anti-inflammatory potential, and improve the anti-inflammatory effects of the extract, a bioinformatics-guided extraction protocol was employed in this study. The potential bioactive candidates were identified by combing network pharmacology analysis, molecular docking, principal components analysis, k-means clustering, and in vitro testing of reference compounds. Our results demonstrated that 66 compounds in CRP could be grouped into four clusters according to their docking score profile against 24 receptors, while the cluster containing flavonoids and phenols might possess a more promising anti-inflammatory function. In addition, in vitro anti-inflammatory tests of the seven reference compounds demonstrated that hesperitin, naringenin, and gardenin B, which were grouped into a cluster containing flavonoids and phenols, significantly decreased LPS-induced NO, TNF-α, and IL-6 production of macrophages. While the compounds outside of that cluster, such as neohesperidin, naringin, hesperidin, and sinensetin showed little effect on alleviating LPS-induced NO and proinflammatory cytokine production. Based on the chemical properties of selected compounds, ethyl acetate (EtOAc) was selected as the solvent for extraction, because of its promising solubility of flavonoids and phenols. Furthermore, the ethanol alcoholic extract was used as a reference. The chemical profiling of EtOAc and crude alcoholic extract by HPLC/MS/MS also demonstrated the decreased abundance of flavonoid glycosides in EtOAc extract but increased abundance of phenols, phenolic acid, and aglycones. In accordance with the prediction, the EtOAc extract of CRP, but not the crude alcoholic extract, significantly decreased the NO, IL-6, and TNF-α production. Taken together, the results suggested selective extraction of phenols and flavonoids rich extract was able to increase the anti-inflammatory potential of CRP partially because of the synergistic effects between flavonoids, phenols, and enriched polymethoxyflavones. Our study might pave the road for the development of ethyl acetate extract of CRP as a novel functional food with anti-inflammatory function.

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“…These findings well fit with the in vivo demonstration that administration of RG7155, a monoclonal antibody that inhibits MCSF-1R activation, to CRC patients led to striking reductions of CSF-1R+CD163+ macrophages in tumor tissues ( 45 ). Moreover, Lee K-H and colleagues showed that oral administration of an active and selective MCSF-1R inhibitor to C57BL/6 mice bearing the MC38 murine colon tumor increased the M1/M2 macrophage ratio and the number of cytotoxic CD8+ T-cells within the tumor, with the downstream effect of delaying the tumor growth ( 46 ). Altogether these data suggest that the pro-tumorigenic effect of IL-34/MCSF-1R axis in the colon is, at least, in part mediated by induction of immunosuppressive TAMs.…”

Section: Role Of Il-34/mcsf-1r Axis In the Differentiation And Functi...mentioning

confidence: 99%

Targeting IL-34/MCSF-1R Axis in Colon Cancer

et al. 2022

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Colorectal carcinoma (CRC) is one of the most common neoplasias in the Western world and it is still one of the most deadly cancers worldwide mainly due to the fact that metastatic CRC is not responsive to current pharmacologic treatment. Identification of pathways that sustain CRC cell behaviour could help develop effective therapeutic compounds. A large body of evidence indicates that colon carcinogenesis is a dynamic process in which multiple cell types present in the tumor microenvironment either stimulate or suppress CRC cell growth, survival, and diffusion mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine initially known for its ability to regulate monocyte/macrophage survival and function, is highly produced in human CRC by both cancer cells and non-tumoral cells. IL-34 function is mainly mediated by interaction with the macrophage colony-stimulating factor-1 receptor (MCSF-1R), which is also over-expressed by CRC cells as well as by tumour-associated macrophages (TAMs) and cancer-associated fibroblasts. IL-34-driven MCSF-1R activation triggers several pro-tumoral functions in the colon. In this article, we review the current understanding of the involvement of IL-34 and its receptor in CRC, with particular attention to the available evidence about the IL-34/MCSF-1R axis-mediated regulation of TAMs and the role of IL-34 and MCSF-1R in promoting cancer resistance to chemotherapy and immunotherapyManuscript Contribution to the FieldIn this review, we highlight the multiple effects of IL-34 and its receptor, macrophage colony-stimulating factor-1 receptor, on the activity of colorectal cancer (CRC) cells and non-tumoral cells, with particular attention to the available data supporting the role of IL-34/MCSF-1R axis in the control of tumor-associated macrophages. The findings summarized in this manuscript could help understand whether targeting IL-34/MCSF-1R can be exploited for therapeutic intervention in CRC.

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Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model

Cited by 27 publications

References 60 publications

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Bioinformatics-Guided Identification of Ethyl Acetate Extract of Citri Reticulatae Pericarpium as a Functional Food Ingredient with Anti-Inflammatory Potential

Targeting IL-34/MCSF-1R Axis in Colon Cancer

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