Fms-related tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expresses on hematopoietic cells. However, FLT3 plays a critical role in both normal and malignant hematopoiesis. According to existing research data, activating mutations of FLT3 can be found in ~30% of acute myeloid leukemia (AML) cases. Moreover, FLT3-ITD is the most common form of FLT3 mutation, with an incidence rate of 15%-35% of patients with AML. Besides, this mutation causes the constitutive activation of FLT3 and therefore activates multiple intracellular signaling molecules, such as PI3K/AKT and MAPK/ERK, which in turn promote the proliferation and inhibit the apoptosis of leukemia cells. However, patients with FLT3-ITD exhibit a high relapse rate, poor clinical prognosis, and lower overall survival.
Several studies have demonstrated that FLT3-ITD is a valid target for the treatment of FLT3-ITD-positive AML. Hence, we will introduce a USP10 inhibitor, Wu-5, which can enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways.
Wu-5 is a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein.
Wu-5 selectively inhibits the viability of FLT3 inhibitor-sensitive (MV4-11, Molm13) and -resistant (MV4-11R) FLT3-ITD-positive AML cells with IC50 of 3.794, 5.056, and 8.386 μM, respectively. In addition, Wu-5 (1-10 μM) dose-dependently induces apoptosis of MV4-11, Molm13, and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD. Besides, Wu-5 directly interactes with and inactivated USP10, the deubiquitinase for FLT3-ITD in vitro (IC50 value= 8.3 µM) and in FLT3-ITD-positive AML cells.
Wu-5 not only has inhibitory activity on FLT3-ITD positive cells when used alone, but also is effective when used in combination with other agents. The combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins. Moreover, Wu-5 can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.
All in all, Wu-5 is a promising USP10 Inhibitor for AML research.