Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition.

The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream of FLT3 signaling. The drug combination induced synergistic inhibition of proliferation, as well as enhanced apoptosis, compared with single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary acute myeloid leukemia (AML) cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control treatment, whereas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared with results in the single-drug and vehicle control groups. Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

(18-Crown-6-κO)(pyrazolato-κN,N')-potassium(I).

The asymmetric unit of the title compound, [K(C(3)H(3)N(2))(C(12)H(24)O(6))], is composed of a potassium cation bonded to the six O atoms of a crown ether mol-ecule and the two N atoms of a pyrazolate anion. The K⋯O distances range from 2.8416 (8) to 3.0025 (8) Å, and the two K⋯N distances are 2.7441 (11) and 2.7654 (11) Å. The K cation is displaced by 0.8437 (4) Šfrom the best plane through the six O atoms. The latter plane is almost perpendicular to the plane of the pyrazolate ring [dihedral angle 83.93 (3)°].

Setting ambiguity in C2/c with dibromidotetrakis(1H-pyrazole-kappaN2)manganese(II) as an example.

trans-Dibromidotetrakis(1H-pyrazole-kappaN(3))manganese(II), [MnBr2(C3H4N2)4], crystallizes in the C2/c space group with the Mn atom located on a centre of inversion. As a result, there is just one half-molecule in the asymmetric unit. Geometric parameters are in the usual ranges. The Mn centre is octahedrally coordinated by four pyrazole residues in the equatorial plane and by two bromide ligands in the axial positions. The molecular conformation is stabilized by N-H...Br hydrogen bonds. The structure of the title compound had already been described [Lumme & Lindell (1987). J. Coord. Chem. 15, 383-392] in a different setting, with the Mn atoms located on inversion centres on Wyckoff position d (1/4, 1/4, 1/2; 3/4, 1/4, 0; 3/4, 3/4, 1/2; 1/4, 3/4, 0). In the conventional setting, however, the Mn atoms are situated on Wyckoff position a (0, 0, 0; 0, 0, 1/2; 1/2, 1/2, 0; 1/2, 1/2, 1/2). In this special case, if the c axis has the same length as the short diagonal of the ac plane, the transformation from one setting into the other yields almost indistinguishable cell parameters, and the possibility of confusion arises. This setting ambiguity could be the reason why two structures in different settings might be taken as polymorphs even though they can easily be transformed. As a result of this, care should always be taken to use the conventional setting.