Structure-based Design, Synthesis, Evaluation, and Crystal Structures of Transition State Analogue Inhibitors of Inosine Monophosphate Cyclohydrolase

摘要: Abstract The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes final step in de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), corresponding nucleoside (2), and (nucleotide) (3), as mimics tetrahedral intermediate cyclization reaction. All compounds are competitive inhibitors against (Ki values = 0.13-0.23 μm) with simple heterocycle 1 exhibiting most potent inhibition 0.13 μm). Crystal structures ATIC complex 2 nucleotide 3 revealed binding modes similar to feedback inhibitor, xanthosine 5′-monophosphate. Surprisingly, simpler had completely different mode was relocated phosphate pocket identified from previous 5′-monophosphate structures. aromatic imidazole ring interacts helix dipole, interaction moiety 3. crystal not only mechanism these compounds, but they now serve platform future inhibitor improvements. Importantly, nucleosidecomplexed structure supports notion lacking negatively charged can still inhibit activity comparable potency phosphate-containing inhibitors. Provocatively, also binds AICAR Tfase domain ATIC, which provides lead compound design simultaneously both active sites this enzyme.