Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the
Liping Liu1,2, Rui Zhu3, Jiacheng Li1,2
1Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
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.
Insights
Researchers developed ZL-Pin13, a potent covalent inhibitor targeting peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1). This compound effectively inhibits cancer-driving pathways and cell proliferation, offering a new tool for Pin1 research.
Area of Science:
- Biochemistry
- Chemical Biology
- Cancer Biology
Background:
- Peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is a crucial enzyme that regulates numerous cancer-driving pathways.
- Aberrant Pin1 activation is a common feature in many human cancers, making it a significant therapeutic target.
Purpose of the Study:
- To identify and develop novel, potent inhibitors of Pin1.
- To elucidate the binding mechanisms of these inhibitors with Pin1.
- To evaluate the efficacy of the developed inhibitors in cancer cells.
Main Methods:
- Screening of an in-house chemical library to identify hit compounds.
- Structure-guided optimization of lead compounds using crystallographic studies.
- Co-crystallization of Pin1 with inhibitors to determine binding modes.
- Cell-based assays to assess the biological activity of inhibitors.
Main Results:
- A novel hit compound, ZL-Pin01, was identified, covalently modifying Pin1 at Cys113.
- Structure-guided optimization yielded ZL-Pin13, a highly potent Pin1 inhibitor (IC50 = 0.067 ± 0.03 μM).
- Co-crystal structures revealed detailed binding interactions and inhibitor-induced conformational changes in Pin1 (e.g., Gln129).
- ZL-Pin13 demonstrated significant inhibition of proliferation and downregulation of Pin1 substrates in MDA-MB-231 cells.
Conclusions:
- ZL-Pin13 is a potent covalent inhibitor of Pin1 with potential therapeutic applications.
- The developed inhibitors and structural data provide valuable tools for further investigation of Pin1's functional roles in cancer.
- This study highlights the potential of targeting Pin1 for cancer therapy.
