Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

Figures & data

Figure 1. FLT3 inhibitors approved by the FDA as AML treatment.

Figure 2. Design of quinazoline derivatives as bioisosteres of the middle phenyl ring-amide-bond.

Scheme 1. Syntheses of 1H-quinazolyl isoxazole-4-carboxamide derivatives. (i) EDC, HOBt, TEA, NH₃ in MeOH, rt; (ii) BH₃-THF, reflux; (iii) benzoyl chloride, CH₂Cl₂, 0 ^oC→ rt; (iv) (1) HCl/H₂O/AcOH, μW, 150 ^oC, 10 min; (2) p-chloranil, toluene, reflux; (v) Fe, AcOH/H₂O/EtOH, 60 ^oC; (vi) 5-methylisoxazole-4-carbonyl chloride, TEA, THF, rt.

Table 1. Enzymatic activity of 5-methyl-N-(2-arylquinazolin-7-yl) isoxazole-4-carboxamide analogues.

Figure 3. (Left) Compound 7d (green) at the active site of FLT3 (PDB: 4RT7); (right) 7e (yellow) at the active site of FLT3 (PDB: 4RT7).

Figure 4. (Left) Compound 7n with equatorial O linkage (orange) at the active site of FLT3 (PDB: 4RT7); (right) compound 7n with axial O linkage (azure) at the active site of FLT3 (PDB: 4RT7).

Table 2. Enzymatic activities of compound 7d against FLT3 mutants.

Kinase	IC50 (µM)
FLT3 (F594_R595 ins R)	0.524
FLT3 (F594_R595 ins EY)	0.495
FLT3 (Y591_V592 ins VDFREYEYD)	0.728
FLT3 (D835Y)	0.228

Figure 5. Kinase profiling according to chemical scaffold. The profiles of the FMS kinase inhibitor [13] and quinazoline derivative 7d (10 μM) are shown.

Figure 6. (left) Docking structures of 7d in FLT3 (PDB: 4RT7) and 7d in FMS (PDB:3LCO).