Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

Eriksson, Anna; Höglund, Martin; Lindhagen, Elin; Åleskog, Anna; Hassan, Sadia; Ekholm, Carina; Fhölenhag, Karin; Jensen, Annika Jenmalm; Löthgren, Agneta; Scobie, Martin; Larsson, Rolf; Parrow, Vendela

doi:10.1016/j.bcp.2010.08.002

Cited by 7 publications

(9 citation statements)

References 43 publications

(33 reference statements)

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“…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. …”

Section: Discussionmentioning

confidence: 99%

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

Engen

Wergeland

Skavland

et al. 2014

JCM

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Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML.

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Section: Discussionmentioning

confidence: 99%

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

Engen

Wergeland

Skavland

et al. 2014

JCM

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“…20 The panel was expanded to a total of 17 cell lines (Supplementary I), whereof five AML cell lines: MV4-11 (naturally occurring FLT3 ITD mutation), 21 Kasumi-1 (t(8;21), activating KIT mutation), 22, 23 HL-60 (capability to differentiate), 24 KG1a (high content of immature CD34-expressing cells) 25 (obtained from American Type Culture Collection; ATCC, Rockville, MD, USA) and MOLM-13 (heterozygote FLT3-ITD mutation, provided by ProQinase). 26 Cells were kept in culture medium appropriate to cell type supplemented with fetal calf serum, glutamine and antibiotics (Sigma-Aldrich Co).…”

Section: Methodsmentioning

confidence: 99%

“…Selection of patient samples was based on sample availability and drugs were run in parallel. Leukemic cells were isolated, as previously described; 20 a proportion of at least 70% viable tumor cells after thawing was required. The sampling was approved by the Ethics Committee of Uppsala University (No 21/93 and 2007/237).…”

Section: Methodsmentioning

confidence: 99%

“…20 We now present a novel compound from this group, AKN-028, which has been investigated with respect to kinase inhibition profile, pharmacokinetics and cytotoxic activity in cell lines, primary tumor cells and the hollow-fiber mouse model. In addition, we have studied the antileukemic activity of AKN-028 in combination with cytarabine or daunorubicin, as well as the importance of FLT3 mutation-status and quantitative FLT3 expression for the cytotoxic response.…”

Section: Introductionmentioning

confidence: 99%

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

Eriksson

Hermanson

Wickström

et al. 2012

Blood Cancer Journal

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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).

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“…Akn-032 (47) is a 2,3-bisaminopyrazine derivative identified as an Flt3 inhibitor (IC 50 = 70 nM) from a high-throughput screen of small molecules [122]. Akn-032 impeded the proliferation of MV4-11 AML cells, but the growth of fibroblast cell lines was not affected by treatment with the compound.…”

Section: Miscellaneous Flt3 Inhibitorsmentioning

confidence: 99%

FMS-like tyrosine kinase 3 inhibitors: a patent review

Lee

Paek²,

Han³

2011

Expert Opinion on Therapeutic Patents

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Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

Abstract: Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low

Cited by 7 publications

References 43 publications

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

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

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

FMS-like tyrosine kinase 3 inhibitors: a patent review

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