Therapy of hematological malignancies is undergoing a paradigm shift. It is away from the traditional chemotherapy towards the targeting of proteins driving the cancer phenotype. The novel therapeutic approach relies on the use of epigenetic drugs. It aims to reverse critical epigenetic events underlying human cancer pathogenesis, particularly abnormalities in DNA methylation and histone modifications. G9a physically interacts with DNA methyltransferase-1 (DNMT1) to coordinate DNA and histone methylation during cell division11 promoting transcriptional silencing of target genes. In this sense, the reduction of both DNA and H3K9 methylation levels leads to the reactivation of tumor suppressor genes and inhibits cancer cell proliferation. In this study, CM-272 is a potent, first-in-class, substrate-competitive, selective and reversible dual small molecules against G9a and DNMTs activity. Furthermore, it significantly prolongs the survival of AML, ALL and DLBCL xenogeneic models.
CM-272 inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. In addition, CM-272 significantly prolongs the survival of AML, ALL and DLBCL xenogeneic models.
CM-272 inhibits G9a, DNMT1, DNMT3A, DNMT3B and GLP with IC50s of 8 nM, 382 nM, 85 nM, 1200nM and 2 nM, respectively. Moreover, CM-272 inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. It inhibits cell proliferation in a dose- and time-dependent manner in CEMO-1, MV4-11, and OCI-Ly10 cell lines. Meanwhile, CM-272 blocks cell cycle progression and induces apoptosis in ALL, AML and DLBCL cell lines. It inhibits CEMO-1 ALL, MV4-11 AML and OCI-Ly10 DLBCL cell lines, with the GI50s of 218 nM, 269 nM, and 455 nM, respectively. In addition, it is associated with a decrease in global levels of H3K9me2 and 5mC. The therapeutic activity of CM-272 relies on the early activation of the type I IFN response in tumor cells. It also potentially leads to the induction of cell-autonomous immunogenic death in tumor cells.
In summary, CM-272 is a first-in-class dual inhibitor of G9a/DNMTs. It is a promising therapeutic tool for unmet needs in hematological tumors.