Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in miceResearch in context
N. Naganna,
Clement Opoku-Temeng,
Eun Yong Choi,
Elizabeth Larocque,
Elizabeth T. Chang,
Brandon A. Carter-Cooper,
Modi Wang,
Sandra E. Torregrosa-Allen,
Bennett D. Elzey,
Rena G. Lapidus,
Herman O. Sintim
Affiliations
N. Naganna
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Clement Opoku-Temeng
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Graduate Program in Biochemistry, University of Maryland, College Park, MD 20742, USA
Eun Yong Choi
University of Maryland School of Medicine, Baltimore, MD, USA
Elizabeth Larocque
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Elizabeth T. Chang
University of Maryland School of Medicine, Baltimore, MD, USA
Brandon A. Carter-Cooper
University of Maryland School of Medicine, Baltimore, MD, USA
Modi Wang
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Sandra E. Torregrosa-Allen
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
Bennett D. Elzey
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
Rena G. Lapidus
University of Maryland School of Medicine, Baltimore, MD, USA
Herman O. Sintim
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Corresponding author at: Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA.
Background: 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 <10%. 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). Inhibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but patients 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 <1 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. Fund: Purdue University, Purdue Institute for Drug Discovery (PIDD), Purdue University Center for Cancer Research, Elks Foundation and NIH P30 CA023168. Keywords: Acute myeloid leukemia, FLT3-ITD (D835Y/F691L) inhibition, Src kinase inhibitors, FLT3 kinase inhibitors, Anti-leukemic effect
