Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products.

Hwangseo Park,Sungwoo Hong,Jinwon Jeon,Kewon Kim,Soyeon Choi

doi:10.3390/ph14030275

Abstract

Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein–ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.

Highlights

Accepted: 15 March 2021The proviral insertion site of Moloney murine leukemia (PIM) kinases belong to a serine/threonine kinase family with three isoforms including PIM1, PIM2, and PIM3. they play the role of enhancing the proliferation of hematopoietic cells upon stimulation by growth factors and cytokines [1], the enforced expression of PIM kinases was responsible for tumorigenesis in transgenic mouse models [2,3]
Using the modified binding free energy function involving an accurate molecular dehydration term, 100 top-scoring compounds were selected as the virtual hits, all of which were commercially available from a compound vendor (InterBioScreen Ltd., https://www.ibscreen.com, accessed on 15 October 2019). All these putative inhibitors were tested for the presence of the inhibitory activity against PIM1 kinase with in vitro radiometric ([γ-33 P]-ATP) kinase assays (Reaction Biology Corp., Malvern, PA, USA)
As a consequence of the virtual and high-throughput screening processes, four natural products were identified as new PIM1 inhibitors

Summary

Introduction

The proviral insertion site of Moloney murine leukemia (PIM) kinases belong to a serine/threonine kinase family with three isoforms including PIM1, PIM2, and PIM3. They play the role of enhancing the proliferation of hematopoietic cells upon stimulation by growth factors and cytokines [1], the enforced expression of PIM kinases was responsible for tumorigenesis in transgenic mouse models [2,3]. The lack of overt abnormality in PIM1-deficient mice supported the usefulness of PIM1 kinase as a target for the development of new anticancer medicines [9]. PIM1 is involved in the acquisition of drug resistance by phosphorylating and stabilizing drug efflux transporters such as breast cancer resistance protein and P-glycoprotein [10,11], further motivating the discovery of potent PIM1 inhibitors.

Methods

Results

Conclusion