The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia

Abstract

Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nℳ), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μℳ). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions

“…Several second generation TKIs, in addition to quizartinib, are under development, offering improved pharmacodynamic and pharmacokinetic properties including increased potency and selectivity towards FLT3-mutated cells [ 80 ]. VX-322 [ 81 ], BPR1J-097 [ 82 ], TT-3002 [ 83 , 84 ], AKN-028 and AKN-032 [ 85 , 86 ] are examples of novel FLT3 inhibitors that are showing promising in vitro and in vivo antileukemia activities.…”

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

“…Eszopiclone Insomnia [24,25] Zopiclone Treatment of sleep disorders [26] Cephalostatin 1 Anticancer [27,28] Favipiravir Antiviral (approved in Japan, influenza; FDA clearance, COVID-19) [29][30][31] (-)-Barrenazine A Anticancer [32] (-)-Barrenazine B Anticancer [32] Alocasin A Anticancer [33] AKN-028 Acute myeloid leukemia [34,35] Acute myeloid leukemia [34,35] Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial [38] 2-Bromo-1-hydroxy phenazine Antibacterial [39] Griseolutein A Antibacterial [40] HP-14 Biofilm-eradicating agent [41] Iodinin Antibacterial [42] Myxin Antibacterial [43] Quinoxidine Antibacterial [44] Dioxidine Antibacterial [44] Anticancer [36,37] Phenazine-1-carboxylic acid Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial [38] 2-Bromo-1-hydroxy phenazine Antibacterial [39] Griseolutein A Antibacterial [40] HP-14 Biofilm-eradicating agent [41] Iodinin Antibacterial [42] Myxin Antibacterial [43] Quinoxidine Antibacterial [44] Dioxidine Antibacterial [44] Antibacterial [38] 2-Bromo-1-hydroxy phenazine Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial…”

Pyrazine and Phenazine Heterocycles: Platforms for Total Synthesis and Drug Discovery

“…The small molecule AKN-028 and the botryllazine natural products demonstrate a diversity of biological activities. AKN-028 ( 14 ) is a novel pyrazine-based tyrosine kinase inhibitor that has produced promising results in preclinical studies against acute myeloid leukemia (AML) [ 19 , 20 ]. Botryllazine A ( 15 ) is a pyrazine-containing natural product isolated from the tunicate Botryllus leachii [ 21 ].…”