Optimization of the fragment binding to hinge region for a potent PIM kinase inhibitor based on N-pyridinyl amide scaffold

The hinge region in the ATP binding site of kinase has become the promising target to design potent inhibitors for Cancer therapy. Among the ongoing development of Pim inhibitors based on N-pyridinyl amide scaffold for acute myeloid leukemia (AML), the structural-activity relationship (SAR) associated with the fragment towards hinge region still remains an open question. Herein, we systematically optimized hinge region-binding heterocycle of Pim kinase inhibitors based on N-pyridinyl amide scaffold. SAR studies revealed that a 2-position nitrogen configuration capable of forming intramolecular hydrogen bond is optimal to stabilize bioactive conformation. The introduction of 6-position amino group on the heterocycle engaged with upper hinge region through hydrogen bond formation with Glu121, achieving sub-nanomolar Pim kinase inhibition. And it was found that the electronegativity of substituents on the ring exerts minimal modulation effects on this key hydrogen bond with Glu121. Whereas 6-aminopyrazine scaffold could strengthen this hydrogen bond interaction by the electron-withdrawing nature of the additional nitrogen atom adjacent to the amino group. These findings finally screened out compound FD2024 (compound 27), which demonstrated potent pan-PIM inhibition and anti-AML efficacy both in vitro and in vivo. This work highlighted the pivotal role of hinge region-binding fragment, specifically the 2-position nitrogen for bioactive conformation and 6-amino group for engaging Glu121 in improving Pim kinase inhibitor potency.

Acute myeloid leukemia; Glu121 residue; Hinge region; N-pyridinyl amide scaffold; PIM inhibitors.