INCB054329, a structurally distinct bromodomain and extraterminal domain (BET) inhibitor, inhibits BRD2-BD1, BRD2-BD2, BRD3-BD1, BRD3-BD2, BRD4-BD1, BRD4-BD2, BRDT-BD1 and BRDT-BD2 with IC50 values of 44 nM, 5 nM, 9 nM, 1 nM, 28 nM, 3 nM, 119 nM and 63 nM respectively.

BRD4 BD1:28 nM, BRD3 BD2:1 nM, BRD2 BD2:5 nM, BRD4 BD2:3 nM, BRD3 BD1:9 nM

INCB054329 shows no significant inhibitory activity against 16 non-BET bromodomains at 3 μM. In a panel of 32 hematologic cancer cell lines derived from acute myeloid leukemia, non-Hodgkin lymphoma, and multiple myeloma, the GI50 of INCB054329 is 152 nM (range, 26-5000 nM). In contrast to tumor cell lines, the GI50 against T cells isolated from non-diseased donors stimulated ex vivo with IL-2 is 2.435 μM. Growth inhibition correlates with a concentration-dependent accumulation of cells in the G1 phase of the cell cycle. INCB054828 is also a selective kinase inhibitor of the FGFR 1, 2, and 3[1]. Treatment with INCB054329 inhibits expression of c-MYC and induced HEXIM1 in myeloma cell lines. In both lymphoma and AML cell lines, INCB054329 induces apoptosis consistent with increased expression of pro-apoptotic regulators[2]. INCB054329 reduces expression of Homologous recombination (HR) components and co-operatively reduces cell growth and increases DNA damage and apoptosis induced by cisplatin and PARPi [3].

INCB054329 exhibits high clearance in mice leading to a short half-life. At exposures that effectively suppressed c-MYC, INCB054329 is found to be efficacious and well tolerated in both the MM1.S and KMS-12-BM xenograft models[1]. In vivo, oral administration of INCB054329 inhibits tumor growth in several hematologic cancers models[2].

Cell lines: DLBCL, AML, Myeloma cells. Incubation Time: 72 h. Method: Cell viability assay

Animal Models: KMS-12-BM tumors established in female Nu/Nu mice. Dosages: 3, 10, 30, or 100 mg/kg. Administration: oral gavage.