Ertabresib

Ertabresib (INCB-057643) is an orally active BET protein inhibitor. Ertabresib blocks gene transcription by targeting the BET protein family, induces cell cycle arrest and apoptosis by downregulating proto-oncogenes such as c-MYC, and additionally reduces the expression of FOXP3 and PD-L1 to improve the immune microenvironment. It also exerts synergistic effects and overcomes drug resistance when combined with chemotherapy and XPO1 inhibitors. Ertabresib can be used in research related to high-grade B-cell lymphoma with MYC and BCL2 rearrangements, pancreatic cancer, pancreatitis, and metastatic castration-resistant prostate cancer^[1][2][3]. IC50 & Target:BET^[1] In Vitro:Ertabresib (INCB-057643) (0.01-5.0 µM; 72 h) exerts a significant cell proliferation-inhibiting effect in prostate cancer cell lines (DU145, PC3, 22Rv1, LNCaP, VCaP) and exhibits low cytotoxicity^[1].
Ertabresib (1 nM-25 µM; 7-12 days) potently inhibits colony formation and prostate sphere formation in prostate cancer cell lines^[1].
Ertabresib (72 h) exerts synergistic or additive effects on inhibiting cell growth in prostate cancer cell lines when combined with Docetaxel (HY-B0011), Olaparib (HY-10162), or Carboplatin (HY-17393)^[1].
Ertabresib (500 nM; washed out after 72 h pretreatment) induces complete recovery of cell growth in 22Rv1 cells, but combined treatment with Docetaxe results in more sustained growth inhibition and reduced clonogenicity^[1].
Ertabresib (1 mM for TMD8; 2.5 mM for OCI-LY19; 24 h) exerts a synergistic effect with Selinexor to downregulate the mRNA and protein expression levels of c-Myc in HGBCL-DH cell lines^[2].
Ertabresib (in combination with Selinexor) induces DNA damage and downregulates the phosphorylation level of DNA damage repair kinases in TP53-mutant TMD8 cells, while it upregulates the expression levels of p53 and its downstream targets in TP53-wild-type OCI-LY19 cells ^[2].
Ertabresib inhibits cell proliferation in pancreatic cancer cell lines (Aspc-1, PANC-1, CAPAN-1, Panc1342, PanAsc 2159) following 72 h treatment^[3].
Ertabresib (250 nM-10 mM; 24 h) increases p27^KIP1 protein expression in pancreatic cancer cells (Aspc-1, PanAsc 2159)^[3].
Ertabresib (500 nM-1 mM; 24 h-72 h) downregulates PD-L1 protein and mRNA expression in tumor-conditioned medium-stimulated mouse macrophage cell line RAW 264.7 and pancreatic cancer cells (Aspc-1, PanAsc 2159)^[3].
Ertabresib (100 nM; 4 days) significantly reduces FOXP3 mRNA expression levels in in vitro-activated mouse primary CD4 T cells^[3].
Ertabresib (72 h) induces G1/G0 cell cycle arrest and reduces the proportion of cells in S/G2 phase in DU145, 22Rv1, and LNCaP cells^[1].
Combination of Ertabresib (72 h) with XPO1 inhibitors (Selinexor (HY-17536) or Eltanexor (HY-100423)) exerts synergistic effects in reducing cell viability and promoting apoptosis across multiple HGBCL-DH cell lines with or without TP53 mutations, such as FN, HF, TMD8, VAL, Toledo, OCI-LY19, EJ, Pfeiffer and WILL2^[2]. In Vivo:Ertabresib (INCB-057643) (3 mg/kg or 10 mg/kg; p.o.; 3 mg/kg twice daily, 7 days a week / 10 mg/kg once daily, 5 days a week; treatment duration of 16 days or longer) significantly inhibits tumor growth and reduces tumor weight in a male Nude Foxn1 mouse model with subcutaneous xenografts of 22Rv1 cells^[1].
Ertabresib (10 mg/kg; p.o.; once daily; 7 days) alleviates pancreatitis, reduces pancreatic weight, decreases infiltrating activated CD4 T cells, and downregulates the expressions of p-STAT3, COX2, and α-SMA, an activation marker of stellate cells, in a caerulein (HY-A0190)-induced acute pancreatitis model in KC mice^[3].
Ertabresib (10 mg/kg; p.o.; once daily; 2 weeks) slows tumor growth, reduces tumor burden, and induces tumor cell apoptosis in a male mouse model bearing subcutaneous xenografts of TMD8 cells (immunodeficient animals pretreated with total body irradiation)^[2].
Ertabresib (10 mg/kg; p.o.; once daily for consecutive 60 days followed by 5 days per week/or 5 days per week for 16 consecutive weeks starting from 4 weeks of age) exerts effects including prolonging survival, reducing the incidence of liver and lung/diaphragm metastases, decreasing the infiltration of total immune cells and CD4 T cells in the pancreas and liver, and downregulating the expression of immunosuppressive molecules FOXP3 and PD-L1 in the tumor microenvironment in a spontaneous pancreatic cancer model with metastasis in KPC transgenic mice^[3].