The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and Aurora kinases

Abstract

Background: Despite the development of several FLT3 inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemias (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways such as those regulated by BTK, aurora kinases, and potentially others in addition to acquired tyrosine kinase domains (TKD) mutations of FLT3 gene. FLT3may not always be a driver mutation. Objective: To evaluate the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, in order to circumvent drug resistance and target FLT3 wild-type (WT) cells. Methods: The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing cell cycle with flow cytometry in vitro, and its anti-leukemia Results: CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo, regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile of FLT3, BTK, and aurora kinases. InFLT3 mutant cells, CG-806 induced G1 phase blockage, while in FLT3WT cells, it resulted in G2/M arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously resulted in a synergistic pro-apoptotic effect in FLT3mutant leukemia cells. Conclusion: The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemia efficacy, regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets

“…The FLT3/BTK/Aurora kinase (AURKs) inhibitor luxeptinib (CG-806), due to its multi-target action, causes the arrest of blasts in G2/M, promotes polyploidy formation, stimulates apoptosis, and inhibits BTK-mediated autophagy, by-passing resistance to FLT3i [33]. Yu et al [34] confirmed these data in immunoblotting analyses of CG-806-treated cell lines. In fact, inhibition of AKT/mTOR/S6K and MAPK results in suppression of p-mTOR, -S6K, and -RB cell proliferation proteins, while inhibition of BTK causes upregulation of p27 and downregulation of G1 phase checkpoint proteins, such as CDK4, CDK6, and c-Myc, blocking FLT3mut cells (MOLM3 and MV14-4) in G1.…”