PROTACFLT3/JAK2/BRD4 Degrader-1 is a PROTAC degrader targeting FLT3, JAK2, and BRD4, with DC50 values of 5.23 nM, 0.678 nM, and 1.17 nM, respectively. It exhibits potent antiproliferative activity against MV4;11 cells (IC50= 0.79 nM) and FLT3-mutated Ba/F3 cells. Additionally, PROTACFLT3/JAK2/BRD4 Degrader-1 induces apoptosis in MV4;11 cells and demonstrates significant antitumor efficacy in an MV4;11 xenograft model established in NOD SCID mice. This compound is applicable for research in acute myeloid leukemia (AML).

BRD4:1.17 nM (DC50)

PROTAC FLT3/JAK2/BRD4 Degrader-1 (Compound 13e) effectively degrades FLT3, JAK2, and BRD4 in MV4;11 cells, with DC 50 values of 5.23 nM, 0.678 nM, and 1.17 nM, respectively. At a concentration of 1 μM over 8 hours, it induces the degradation of these proteins via the ubiquitin-proteasome system (UPS), relying on cereblon and the proteasome. Additionally, PROTAC FLT3/JAK2/BRD4 Degrader-1 inhibits proliferation in MV4;11 cells with an IC 50 of 0.79 nM at concentrations from 0.00001 to 1000 nM over 96 hours. The compound also exhibits potent antiproliferative effects on Ba/F3 cells transformed with FLT3 mutations, including FLT3-ITD-D835Y (IC 50 = 35.64 nM), FLT3-ITD-F691L (IC 50 = 24.34 nM), FLT3-ITD-N676D (IC 50 = 43.71 nM), FLT3-ITD-D835V (IC 50 = 6.63 nM), FLT3-ITD-Y842C (IC 50 = 8.80 nM), and FLT3-ITD (IC 50 = 28.62 nM) over 96 hours. Furthermore, within 48 hours and at concentrations ranging from 1 to 1000 nM, it induces over 70% apoptosis in MV4;11 cells.

PROTAC FLT3/JAK2/BRD4 Degrader-1 (Compound 13e) administered intraperitoneally at 10 mg/kg once daily for 21 days demonstrates significant antitumor activity in an MV4;11 xenograft model within NOD SCID mice.