Epigenetic Inhibitor F5446

Development of SUV39H1-selective inhibitor F5446 for colorectal cancer immunotherapy

Intellectual Property

Patent: US 10,577,371 B2. Small Molecule Histone Methyltransfease SUV39H1 Inhibitor and Uses Thereof. Granted on March 3, 2020.

Despite the breakthrough of immune checkpoint inhibitor (ICI) immunotherapy in treatment of human cancer, human colorectal cancer stands out as one of the few human cancers that do not respond to ICI immunotherapy. In human colorectal cancer, only the microsatellite instable (MSI-H) subtype, which accounts for only 10-15% of all human colorectal cancer cases, responds to PD-(L)1-based ICI immunotherapy. The vast majority (85-90%) of colorectal cancer is the microsatellite stable (MSS) subtype that does not respond to ICI immunotherapy. PD-(L)1 blockade-based ICI immunotherapy activates cytotoxic T lymphocytes (CTLs) by inhibiting PD-L1-mediated immune suppression. The activated CTLs then target tumor cells to induce tumor cell death. Therefore, two factors are essential for PD-(L)1 blockade efficacy: 1) CTLs must be activated/functional; and 2) the target tumor cells must be sensitive to cell death induction. Colorectal cancer cells, especially human metastatic colorectal cancer cells, are highly resistant to cell death induction. Literate and our published data indicates that tumor-infiltrating CTLs are functionally impaired in human MSS colorectal cancer. It is apparent that an agent with dual functions in sensitizing tumor cells to cell death induction and in activating T cells is needed to overcome human colorectal cancer resistance to ICI immunotherapy.

      SUV39H1 is a histone 3 lysine 9 (H3K9) site-specific histone methyltransferase that catalyzes H3K9me3. Recent literature indicates that SUV39H1 plays an essential role in silencing T cell memory regulatory genes during viral infection in mice. We determined that SUV39H1 is an epigenetic repressor of Gzmb, the gene that encodes granzyme B, the essential cytotoxic effector molecule of tumor-reactive CTLs. Emerging experimental data indicates that in the absence of Suv39h1, PD-1 blockade immunotherapy induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B-producing CTLs that express negative checkpoint molecules, but do not reach final exhaustion in melanoma, suggesting that CTL responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in tumor. Targeting SUV39H1 is therefore potentially an effective approach to activate CTLs in the tumor microenvironment. Furthermore, recent literatures show that genetic disruption of SUV39H1 enhances the early expansion, long-term persistence, and overall antitumor efficacy of human CAR T cells in leukemia and prostate cancer models. Inactivation of SUV39H1 enhances BBz-CAR cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated CD19+ lung tumor and HER2+ ovarian tumor models up to several months after CAR T-cell infusion. SUV39H1 is therefore a potent negative regulator of T cell activation and function in the tumor microenvironment. On the other hand, our published data determined that SUV39H1 expression is significantly higher in human colon carcinoma tissues than in normal colon tissues. Our published data further determined that H3K9me3 is enriched in the promoter of the death receptor FAS in colon tumor cells and inhibition of SUV39H1 increased colon tumor cell sensitivity to FasL-induced cell death. These findings determine that SUV39H1 confer colon tumor cell resistance to cell death induction by T cells.

      Based on these scientific promises, Chemedimmune Inc. is developing the SUV39H1-selective small molecule inhibitor F5446 to re-activate CTL effector function and to restore human colorectal cancer cell sensitivity to cell death induction. F5446 is therefore expected to overcome human colorectal cancer resistance to PD-(L)1 blockade immunotherapy.

Suv39h1 KO mice have no obvious phenotypes, indicating that a SUV39H1-selective inhibitor is likely a safe agent. 

F5446 mechanism of action: F5446 targets both tumor cells and T cells: 1) F5446 activates the Fas death pathway in tumor cells to sensitize tumor cells to FasL-induced cytotoxicity by T cells; and 2) F5446 increases T cell effector expression to boost T cell function.


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