Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting‑1 (Pin1)

The unique proline isomerase peptidyl-prolyl
isomerase NIMA-interacting-1
(Pin1) is reported to activate numerous cancer-driving pathways simultaneously,
and aberrant Pin1 activation is present in many human cancers. Here,
we identified a novel hit compound, ZL-Pin01, that covalently
modified Pin1 at Cys113 with an half-maximal inhibitory concentration
(IC50) of 1.33 ± 0.07 μM through screening an
in-house library. Crystallographic study drove the process of structure-guided
optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 ± 0.03 μM. We obtained
four co-crystal structures of Pin1 complexed with inhibitors that
elucidated the detailed binding mode of the derivatives with Pin1.
Interestingly, the co-crystal of Pin1 with ZL-Pin13 obtained
by co-crystallization revealed the conformational change of Gln129
induced by the inhibitor. Furthermore, ZL-Pin13 effectively
inhibited the proliferation and downregulated the Pin1 substrates
in MDA-MB-231 cells. Collectively, we developed a potent covalent
inhibitor of Pin1, ZL-Pin13, which could be an effective
probe for studying the functional roles of Pin1.