Discovery of Novel Small-Molecule Inhibitors of PD-1/PD-L1 Interaction via Structural Simplification Strategy.

Hongbo Zhang,Huijie Du,Shihui Huang,Yu Xia,Yungen Xu,Chunqiu Yu,Hui Li,Qihua Zhu,Jinchang Liu,Yi Zou

doi:10.3390/molecules26113347

Hongbo Zhang, Huijie Du + Show 8 more

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https://doi.org/10.3390/molecules26113347

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Abstract

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.

Highlights

Programmed cell-death receptor (PD-1) and programmed cell death-ligand 1 (PD-L1)inhibitors have achieved significant success in the oncology community both preclinically and clinically [1,2,3]
In our pursuit of novel small molecule inhibitors targeting the programmed cell death 1 (PD-1)/PD-L1 pathway, we focused our effort on designing molecules with better drug-likeness property
BMS-1058 (IC50 = 0.48 nM) and BMS-202 (IC50 = 18 nM), which inhibited the PD-1/PD-L1 interaction in HTRF binding assay, were chosen as the template compounds for structural optimization

Summary

Introduction

Programmed cell-death receptor (PD-1) and programmed cell death-ligand 1 (PD-L1)inhibitors have achieved significant success in the oncology community both preclinically and clinically [1,2,3]. In the past few years, several monoclonal antibodies (mAbs) targeting PD-1 or PD-L1 have been approved in clinical use by the U.S Food and Drug Administration (FDA) [9], exhibiting significant benefits with durable clinical responses and acceptable treatment-related toxicities in several types of solid tumors [10,11,12]. These mAbs have transformed cancer immunotherapy forever, they still exhibit several disadvantages such as very long half-life, immune-related adverse effects (irAEs), low permeability, immunogenicity, complex production process, and exorbitant treatment costs from another perspective [13]. Among the reported immunological adverse events, the overall incidences of allgrade66.0%

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