PROTACFLT3/CHK1 Degrader-1 is a PROTAC agent targeting FLT3 and CHK1, with DC50 values of 5.88 nM (FLT3) and 4.17 nM (CHK1). It inhibits the phosphorylation of downstream signaling effectors STAT5(Tyr694), AKT(Ser473), and ERK(Tyr204) of FLT3, reduces c-Myc protein levels, and maintains p53 protein expression. Additionally, PROTACFLT3/CHK1 Degrader-1 induces apoptosis in MV-4-11 cells and demonstrates significant antitumor activity in mice with MV-4-11 xenografts. This compound is applicable in acute myeloid leukemia (AML) research.

Chk1:4.17 nM (DC50)

PROTAC FLT3/CHK1 Degrader-1 (Compound A28) demonstrates a concentration-dependent degradation of FLT3 and CHK1 in MV-4-11 cells, with DC50 values of 5.88 nM for FLT3 and 4.17 nM for CHK1. At concentrations of 5-100 nM over 0-12 hours, it downregulates FLT3 and inhibits phosphorylation of downstream effectors such as STAT5 (Tyr694), AKT (Ser473), and ERK (Tyr204). Additionally, this compound degrades CHK1, downregulates c-Myc, and maintains p53 expression in the same cell line. It shows strong antiproliferative activity against FLT3-mutant cells (MV-4-11, MOLM-13, BaF3-FLT3-F691L/D835V/D835F/ITD/ITD/D835Y), while exhibiting weaker activity against non-FLT3-mutant cancer cells (THP-1, TF-1, HL-60). Furthermore, PROTAC FLT3/CHK1 Degrader-1 induces apoptosis in MV-4-11 cells at 1-5 μM over 24 hours.

In mice with MV-4-11 subcutaneous xenografts, PROTAC FLT3/CHK1 Degrader-1 (Compound A28) administered intravenously at a dose of 5-10 mg/kg once a week for 21 days demonstrates significant tumor growth inhibition.