Source: http://chemedimmune.com/
Timestamp: 2019-04-20 02:37:44+00:00

Document:
COMPANY MISSION IS TO DEVELOP THERAPEUTIC AGENTS THAT SENSITIZE CANCER CELLS TO IMMUNE CELLS.
1. Development of the small-molecule PD-L1 and PD-1 interaction blockers for cancer immunotherapy.
Lead agents: PSR-E4, PSR-E6, and PSR-H9.
1. Priscilla S. Redd, Chunwan Lu, John D. Klement, Mohammed L. Ibrahim, Gang Zhou, Takumi Kumai, Esteban Celis, and Kebin Liu. 2018. H3K4me3 mediates the NF-kB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells. OncoImmunology. In Press.
3.Chunwan Lu and Kebin Liu. 2017. Epigenetic regulation of PD-L1 expression and pancreatic cancer response to checkpoint immunotherapy. Trans Cancer Res. 6: S652-S654.
4.Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Savage, Jennifer L. Waller, Maria E. Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu. 2017. The MLL1-H3K4me3 Axis-Mediated Up-Regulation of PD-L1 Contributes to Pancreatic Cancer Immune Evasion. J Natl Cancer Inst (JNCI). 109:djw283.
PD-L1/PD-1 antibodies have shown a remarkable and durable efficacy in human patients with various types of cancers. The FDA has approved antibody-based drugs KEYTRUDA and OPDIVO for the treatment of human cancers including advanced melanoma and non-small cell lung carcinoma. CheMedImmune used structure-based virtual library screening approach and designed a series of small molecules that interrupt PD-L1 and PD-1 interactions. Using biochemical, cellular and immunological assays developed at Georgia Cancer Center and CheMedImmune Inc., several small molecules that can effectively disrupt PD-L1 binding to PD-1 of activated T cells in vitro have been identified.
The current effort is focused on testing the efficacy of these novel inhibitors in their enhancement of tumor-reactive T cell function in tumor-bearing mouse models.
US patent application No. 62/559,747 and No. 62/649,285. Filed on September 18, 2017.
US patent application title: Small Molecule Histone Methyltransfease SUV39H1 Inhibitor and Uses Thereof.
1. Chunwan Lu, Dafeng Yang, Maria E. Sabbatini, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric Pearce, and Kebin Liu. 2018. Contrasting Roles of H3K4me3 and H3K9me3 in Regulation of Apoptosis and Gemcitabine Resistance in Human Pancreatic Cancer Cells. BMC Cancer. 18:149.
2. Chunwan Lu and Kebin Liu. 2017. Epigenetic regulation of PD-L1 expression and pancreatic cancer response to checkpoint immunotherapy. Trans Cancer Res. 6:S652-S654.
3. Priscilla S. Redd, Mohammed Ibrahim, Sarah K. Sharman, Amy V. Paschall, Dafeng Yang, and Kebin Liu. 2017. SETD1B activate iNOS expression in myeloid-derived suppressor cells. Cancer Res. 77:2834-2843.
4. Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Savage, Jennifer L. Waller, Maria E. Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu. 2017. The MLL1-H3K4me3 Axis-Mediated Up-Regulation of PD-L1 Contributes to Pancreatic Cancer Immune Evasion. J Natl Cancer Inst (JNCI). 109:djw283.
5. Amy V. Paschall and Kebin Liu, 2015. Epigenetic and Immune Regulation of Colorectal Cancer Stem Cells. Curr Colorectal Cancer Rep. 11:414-421.
6. Amy V. Paschall, Dafeng Yang, Chunwan Lu, Jeong-Hyeon Choi, Xia Li, Feiyan Liu, Mario Figueroa, Nicholas H. Oberlies, Cedric Pearce, Wendy B. Bollag, Asha Nayak-Kapoor, Kebin Liu. 2015. H3K9 Trimethylation Silences Fas Expression to Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance. Immunol. 195:1868-82.
7. Amy V. Paschall and Kebin Liu. 2015. Epigenetic Regulation of Apoptosis and Cell Cycle Regulatory Genes in Human Colon Carcinoma Cells. Genomics Data. 5:189-191.
H3K9me3 is a chromatin histone modification marker that controls silencing of tumor suppressors. SUV39H1 is the histone methyltransferase (HMTase) that catalyzes H3K9me3. Based in data mining of the TCGA database, SUV39H1 is highly elevated in almost all human tumor tissues as compared to the respective normal tissues. We therefore aimed at developing a small molecule SUV39H1 inhibitor. Molecular docking program Autodock Vina was used to screen the NCI small chemical virtual library based on the SET domain structure of human SUV39H1 protein. The top 43 hits were selected and tested for inhibition of human SUV39H1 enzyme activity in vitro. Compound A8 and H1 exhibited inhibitory activity against recombinant SUV39H1. These two compounds were further tested at Reaction Biology Corp (Malvern, PA). Compound A8 was then selected and structurally modified in collaboration with a Medicinal Chemist. A chemical synthesis procedure was then developed and optimized for this A8 derivative termed F5446 through contract service at LeadGen Labs (Orange, CT). We now have the procedure to synthesize F5446 in large quantity for preclinical studies. F5446 has a molecular weight of 552.95 and exhibits an EC50 of 0.496 µM in in vitro enzyme activity assay. We have now performed extensive in vitro and in vivo studies and determined that F5446 is an effective SUV39H1-H3K9me3 inhibitor in vivo and a potent immunotherapeutic small molecule agent.
The goal is to move F5446 to Phase I human clinical trials for human cancer immunotherapy. Although most of the preliminary data were obtained in colon cancer. We strongly believe that, like anti-PD-1 mAb, F5446 should be effective for most human cancers. We have formed CheMedImmune Inc. to further develop and commercialize F5446 as an anti-cancer immunotherapeutic agent.
Lead agents: IG4, IG7, IG14, IG17 and IG19.
US patent application title: Ceramide Analogs.
1. Genevieve L. Coe, Priscilla S. Redd, Amy V. Paschall, Chunwan Lu, Lilly Gu, Thomas Albers, Iryna O. Lebedyeva, and Kebin Liu. 2016. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. Rep. 6:30816. PMCID: PMC4973238.
2. Feiyan Liu, Xia Li, Chunwan Lu, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Brendan Marshall, Patricia V. Schoenlein, Iryna O. Lebedyeva and Kebin Liu. Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells. Oncotarget. 7:83907-83925. PMCID: PMC27880732.
3. Amy V Paschall, Mary A Zimmerman, Christina M Torres, Dafeng Yang, May R Chen, Xia Li, Erhard Bieberich, Aiping Bai, Jacek Bielawski, Alicja Bielawska and Kebin Liu. 2014. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression. BMC Cancer. 14:24. PMCID: PMC3898374.
4. Xiaolin Hu, Dafeng Yang, Mary Zimmerman, Feiyan Liu, Jine Yang, Swati Kannan, Andreas Burchert, Zdzislaw Szulc, Alicja Bielawska, Keiko Ozato, Kapil Bhalla, and Kebin Liu. 2011. IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia. Cancer Res. 71:2882-91. PMCID: PMC3078194.
The emerging clinical success of anti-PD-1/PD-L1-based immune checkpoint inhibitor immunotherapy in the last few years has significantly extended survival of many types of human cancer patients. However, colorectal cancer (CRC), except for the small subset (4%) microsatellite instable (MSI) CRC, stands out as one of the few human cancers where anti-PD-1/PD-L1 immunotherapy has been unsuccessful. The mechanism under CRC non-response to anti-PD-1 is unknown. It is generally believed that the expression level of PD-L1 is a response predictor to anti-PD-1/PD-L1 immunotherapy. In the literature, the expression levels of PD-L1 in human CRC cells are controversial and it has been proposed that the lack of PD-L1 expression is the underlying mechanism of CRC non-response to anti-PD-1/PD-L1 immunotherapy. However, our preliminary data challenge this notion. Using a recently developed highly specific and FDA-approved anti-PD-L1 mAb, we have demonstrated that PD-L1 is abundantly expressed in tumor cells and myeloid-derived suppressor cells in human colon carcinoma. Furthermore, our preliminary data demonstrated that anti-PD-1 and anti-PD-L1 immunotherapy can effectively activate cytotoxic T lymphocytes (CTLs). In addition, we have shown that FasL of CTLs is essential for tumor growth control in an orthotopic colon cancer mouse model. Because CTLs suppress tumor growth through inducing tumor cell death, our observations suggest that CRC resistance to cell death is an underlying mechanism of CRC resistance to anti-PD-1/PD-L1 immunotherapy.
Although it has been shown that Fas may promote tumor growth under certain cellular context, the best known Fas function is mediating FasL-induced apoptosis. The Fas-FasL pathway is one of the two effector mechanisms that CTLs use to kill target cells, including tumor cells. Fas is the death receptor that is often down-regulated in human colon carcinoma cells. The Fas receptor exists as a trimeric membrane-bound surface receptor and its clustering is essential for Fas function. Therefore, enhancing Fas receptor clustering is potentially a more effective approach to increase Fas receptor affinity to FasL of activated CTLs to booste CTL efficacy in cancer immunotherapy.
Ceramide is a key secondary messenger that mediates multiple cellular functions. Compelling experimental data have shown that ceramide deregulation is a key f actor in tumor progression and cancer cell resistance to chemotherapeutic agents and radiation, which has led to extensive studies to target the ceramide metabolism pathways for development of potential anticancer therapies. However, an ignored and potentially significant function of ceramide is that ceramide can effectively enhance Fas receptor clustering and oligomerization.
We have recently discovered that ceramide plays an essential role in Fas-mediated apoptosis of tumor cells. Fas is a death receptor expressed on tumor cell surface. FasL is the physiological ligand of Fas and is expressed on the surface of activated T cells. The Fas-FasL pathway plays an essential role in host cancer immune surveillance. Tumor cells often use silencing Fas expression to escape from host cancer immune surveillance. We discovered that although Fas is silenced in tumor cells, low level of Fas is still expressed on tumor cell surface and ceramide can effectively increase Fas oligomerization to increase tumor cell sensitivity to FasL-induced cell death. Based on this discovery, we have designed a series of ceramide analogs as potential enhancer of Fas-mediated apoptosis of colon cancer cells. We have extensively tested these analogs and developed 5 ceramide analogs that significantly increase human colon carcinoma cell sensitivity to FasL-induced tumor cell death by tumor-specific T cells in vitro.
Current effort is to test these 5 compounds in vivo cancer immunotherapy mouse tumor models to develop these analogs as enhancer for anti-PD-L1/PD-1 mAb- and T cell adoptive transfer-based cancer immunotherapy.
© 2016 CheMedImmune Inc. All rights reserved.

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 application No. 62
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