SF2523: Dual PI3K/BRD4 Inhibitor Blocks Tumor Immunosuppression and Promotes Adaptive Immune Responses in Cancer

Joshi, Shweta; Singh, Alok R.; Liu, Kevin X.; Pham, Timothy V.; Zulcic, Muamera; Skola, Dylan; Chun, Hyun Bae; Glass, Christopher K.; Morales, Guillermo; Garlich, Joseph R.; Durden, Donald L.

doi:10.1158/1535-7163.mct-18-1206

Cited by 37 publications

(46 citation statements)

References 32 publications

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“…Another target for negative regulation of antitumor immunity recently discovered and reported by our group and other laboratories is the PI3K signaling pathway, in particular p110g in MÈs (6,17). Our laboratory has reported that p110g in MÈs promotes expression of protumorigenic MÈs in TME and our pan PI3K/BRD4 inhibitor SF1126 or SF2523, blocked tumor growth and MÈ-mediated immunosuppression in tumors (17,18). Furthermore, Syk kinase is required for activation of PI3K in MÈs and B cells (19,20).…”

Section: Introductionmentioning

confidence: 67%

“…2A). In contrast, expression of immunostimulatory genes (6,18) was significantly enhanced in the TAMs from Syk MC-KO animals compared with that of Syk MC-WT tumors ( Fig. 2A).…”

Section: Syk Kinase Promotes Mè Polarization and Immunosuppressionmentioning

confidence: 91%

“…We next investigated whether Syk deletion in MÈs alters expression of genes associated with immunosuppression and tumor progression. The expression of genes that mediates immunosuppression in TME (6,18) were significantly higher in TAMs isolated from LLC tumors grown in Syk MC-WT animals compared with that of Syk MC-KO animals ( Fig. 2A).…”

Section: Syk Kinase Promotes Mè Polarization and Immunosuppressionmentioning

confidence: 99%

“…In another experiment, B16-OVA cells were injected in C57BL/6 WT mice and when tumors reached 100 mm 3 , mice were treated with 200 mg anti-PDL1 antibodies either alone or in combination with 40 mg/kg R788 as described in Supplementary Methods. CD8 depletion and MÈ depletion experiments were performed as described earlier (18) and in Supplementary Methods.…”

Section: In Vivo Tumor Experimentsmentioning

confidence: 99%

“…Tumors were isolated, minced, and then enzymatically dissociated in collagenase digestion cocktail at 37 C for 30-45 minutes and cells were prepared for magnetic bead purification of CD11b, or CD90.2 cells or for flow cytometry as reported before (16,18). For mass cytometry, cells were subsequently stained with metal-labeled antibodies cocktail and run on mass cytometer (CyTOF, Fluidigm) as described in Supplementary Methods.…”

Section: Isolation Of Single Cells From Tumors Flow Cytometry and Mmentioning

confidence: 99%

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Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Joshi

Liu

Zulcic

et al. 2020

Molecular Cancer Therapeutics

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◥ Macrophages (MÈ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MÈs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kg has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MÈ Syk-PI3K axis drives polarization of immunosuppressive MÈs that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3Kg in MÈs promotes a proinflammatory MÈ phenotype, restores CD8 þ T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposaseaccessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow-derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-kB motif in Syk MC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MÈs to suppress tumor growth. Finally, we have developed in silico the "first-in-class" dual Syk/ PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.

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Section: Introductionmentioning

confidence: 67%

“…2A). In contrast, expression of immunostimulatory genes (6,18) was significantly enhanced in the TAMs from Syk MC-KO animals compared with that of Syk MC-WT tumors ( Fig. 2A).…”

Section: Syk Kinase Promotes Mè Polarization and Immunosuppressionmentioning

confidence: 91%

Section: Syk Kinase Promotes Mè Polarization and Immunosuppressionmentioning

confidence: 99%

Section: In Vivo Tumor Experimentsmentioning

confidence: 99%

Section: Isolation Of Single Cells From Tumors Flow Cytometry and Mmentioning

confidence: 99%

See 3 more Smart Citations

Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Joshi

Liu

Zulcic

et al. 2020

Molecular Cancer Therapeutics

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LC–MS/MS method for the quantitation of a dual PI3K/BRD4 inhibitor SF2523 in mouse plasma: Application to plasma protein binding and metabolism studies

Bala

Chhonker

Morales

et al. 2023

Biomedical Chromatography

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A sensitive and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of dual PI3K/BRD4 inhibitor SF2523 in mouse plasma. The analysis was performed on a UPLC system connected to a Shimadzu 8060 mass spectrometer by electrospray ionization in positive multiple reaction monitoring mode. Chromatographic separation was carried out on an ACE Excel C 18 column with a gradient elution containing 0.1% formic acid and methanol as the mobile phase. The linearity was conducted in the concentration range 0.1-500 ng/ml for SF2523 in 100 μl of plasma. The inter-and intra-batch precision (RSD) were both lower than 13.5%, with the accuracy (percentage bias) ranging from À10.03 to 11.56%. The validated method was successfully applied to plasma protein binding and in vitro metabolism studies. SF2523 was highly bound to mouse plasma proteins (>95% bound). Utilizing mouse S9 fractions, a total of seven phase I and II metabolites were identified with hydroxylation found to be the major metabolic pathway. Metabolite identification included analysis of retention behaviors, molecular weight changes and MS/MS fragment patterns of SF2523 and the metabolites. This newly developed and validated method allows the rapid and easy determination of the SF2523 concentration with high sensitivity in a low sample volume and can be applied to future pre-clinical studies.

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The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers

Ren

Xiong

et al. 2023

MedComm

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Myeloid‐derived suppressor cells (MDSCs) are an immature group of myeloid‐derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC‐targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor‐infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC‐targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small‐molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in‐depth understanding of MDSC‐targeted therapy could provide more possibilities for the treatment of cancer.

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SF2523: Dual PI3K/BRD4 Inhibitor Blocks Tumor Immunosuppression and Promotes Adaptive Immune Responses in Cancer

Cited by 37 publications

References 32 publications

Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression

LC–MS/MS method for the quantitation of a dual PI3K/BRD4 inhibitor SF2523 in mouse plasma: Application to plasma protein binding and metabolism studies

The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers

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