Abstract
B
ackground: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to b10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). In- hibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but pa- tients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691 L mutations.
Methods: Alkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth. Findings: The compounds inhibited FLT3 kinase activity at low nanomolar concentrations. The lead compound, HSN431, also inhibited Src kinase activity. The compounds potently inhibited the viability of MV4–11 and MOLM-14 AML cells with IC50 values b1 nM. Furthermore, the viability of drug-resistant AML cells harboring the D835Y and F691 L mutations were potently inhibited. In vivo efficacy studies in mice demonstrated that the compounds could drastically reduce AML proliferation in mice.
Interpretation: Compounds that inhibit FLT3 and downstream targets like Src (for example HSN431) are good leads for development as anti-AML agents.
Keywords
Acute myeloid leukemia, FLT3-ITD (D835Y/F691L) inhibition, src kinase inhibitors, FLT3 kinase inhibitors, anti-leukemic effect
Date of this Version
1-25-2019
DOI
10.1016/j.ebiom.2019.01.012
Recommended Citation
Naganna N, Opoku-Temeng C, Choi EY, Larocque E, Chang ET, Carter-Cooper BA, Wang M, Torregrosa-Allen SE, Elzey BD, Lapidus RG, Sintim HO. Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice. EBioMedicine. 2019 Feb;40:231-239. doi: 10.1016/j.ebiom.2019.01.012. Epub 2019 Jan 25. PMID: 30686755; PMCID: PMC6413339.
Comments
This is the publishers version of Naganna N, Opoku-Temeng C, Choi EY, Larocque E, Chang ET, Carter-Cooper BA, Wang M, Torregrosa-Allen SE, Elzey BD, Lapidus RG, Sintim HO. Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice. EBioMedicine. 2019 Feb;40:231-239. doi: 10.1016/j.ebiom.2019.01.012. Epub 2019 Jan 25. PMID: 30686755; PMCID: PMC6413339.