Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Abstract

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

“…A 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7c ) inhibited the proliferation and increased apoptosis of FLT3 -ITD cells in vitro and reduced the in vivo growth of tumors obtained by xenotransplantation of the FLT3 -ITD MV4-11 AML cell line, without causing obvious toxicities [ 54 ]. Similar to other FLT3 inhibitors [ 80 ], compound 7c induced downregulation of DDR genes belonging to the homologous recombination (BRCA1, BRCA2, BARD1 and RAD51) and non-homologous end joining (XRCC4, XRCC5 and XRCC6) pathways and accumulation of DNA damage [ 54 ]. As a consequence, compound 7c sensitized FLT3 -ITD AML cells to treatment with the PARP inhibitor olaparib [ 54 , 81 ].…”

“…Similar to other FLT3 inhibitors [ 80 ], compound 7c induced downregulation of DDR genes belonging to the homologous recombination (BRCA1, BRCA2, BARD1 and RAD51) and non-homologous end joining (XRCC4, XRCC5 and XRCC6) pathways and accumulation of DNA damage [ 54 ]. As a consequence, compound 7c sensitized FLT3 -ITD AML cells to treatment with the PARP inhibitor olaparib [ 54 , 81 ].…”

DNA damage accumulation and repair defects in FLT3‐ITD acute myeloid leukemia: Implications for clonal evolution and disease progression

“…Meanwhile, the FLT3 inhibitor AIU2008 also downregulated the HR and NHEJ pathways, synergizing with PARP inhibitors to inhibit leukemic cell growth 70 . Other compounds with FLT3 inhibitory activity showed synthetic lethality with PARP inhibitors involving the aforementioned DNA repair pathways, inhibition of STAT5 signaling, and YAP1 deacetylation 71,72 . On the other hand, use of a DNA‐PKcs inhibitor such as M3814 was shown to enhance DNA damage signaling, synergize the effects of topoisomerase II inhibitors and sensitize AML cells to P53‐dependent apoptosis, regardless of FLT3 mutational status, the surrounding cellular context, and its combination with cytarabine 73 .…”