PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.
Abstract
Objectives This study aims to identify novel small-molecule inhibitors that target both PD-L1 and EZH2 to enhance colorectal cancer immunotherapy. Methods A combination of computer-aided molecular simulation, homogeneous time-resolved fluorescence (HTRF) assays, biolayer interferometry (BLI) assays, microscale thermophoresis (MST), and MTase-Glo methyltransferase assays was used to identify compounds with dual-targeting potential. Results Compound PE-1 exhibited potent inhibitory activity against the PD-1/PD-L1 interaction (IC50 = 48.1 nM) and showed strong EZH2 methyltransferase inhibitory effects, with an IC50 of 101.2 nM. BLI and MST further confirmed that PE-1 can effectively bind to both PD-L1 and EZH2 at the molecular level, supporting its bifunctional targeting capability. Importantly, compound PE-1 demonstrated significant activity in a PD-1/PD-L1 NFAT reporter bioassay, dose-dependently enhancing luciferase activity (EC50 = 0.61 μM), indicating effective blockade of the PD-1/PD-L1 pathway and reactivation of T-cell NFAT signaling. Notably, PE-1 demonstrated favorable in vivo pharmacokinetic properties, including a satisfactory oral bioavailability of 58.4%. In syngeneic tumor models, oral administration of PE-1 elicited substantial anti-tumor efficacy, with tumor growth inhibition (TGI) reaching 69.9% in CT26 tumors. Conclusions PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.
CP-1 exhibits balanced, dual-nanomolar inhibitory activity against PD-L1 and CD73 and displays potent immunomodulatory effects at the cellular level and serves as a promising lead candidate for developing novel bifunctional agents to advance tumor immunotherapy.
Jing-Jing Du, Sen Wu, Shiyun Cheng et al.· Frontiers in Immunology· 0 citations
Inhibiting overexpressed key immunoregulatory proteins, programmed
death-ligand 1 (PD-L1) and V-domain immunoglobulin suppressor of T cell activation (VISTA),
represents a critical strategy for restoring antitumor immunity. These proteins are upregulated under
hypoxic conditions, leading to immune evasion and drug resistance to monotherapy.
In this study, a comprehensive computational workflow, including structure-based pharmacophore
screening and validation, molecular docking, predictive toxicity profiling, and molecular
dynamics (MD) simulations, was used to explore a marine database for compounds that bind
PD-L1 and VISTA simultaneously.
The retrospective pharmacophore validation of known actives and decoys confirmed the
discriminatory reliability of both PD-L1 and VISTA models. From the common pharmacophore
alignment of PD-L1 and VISTA models, 235 marine compounds exhibited RMSD values <2.0 Å.
Based on the molecular docking screening of these common hits, CMNPD14606, CMNPD20027,
and CMNPD20697 were found to have higher affinities than the reference P17 and S8. Additionally,
these hits demonstrated favorable physicochemical profiles; however, the in-silico toxicity profiling
revealed modest-to-high genotoxicity and mutagenicity liabilities for all three compounds,
which represent key safety limitations. The MD simulations, performed in triplicate for up to 100
ns, confirmed MD stability across independent replicates.
The identification of marine-derived compounds addresses the need to overcome resistance
to single-checkpoint immunotherapy. Accordingly, these compounds are regarded as earlystage
lead scaffolds requiring structural optimization rather than hits with acceptable overall safety
profiles.
These results suggest the development of dual-targeting PD-L1/VISTA compounds
that warrant lead optimization to mitigate toxicity risks before further experimental investigation.
Jeevan Patra, Surya Nath Pandey, Harishchandra Verma et al.· Current Chemical Biology· 0 citations
Resistance to monotherapy remains a major challenge in the treatment of nonsmall cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. To address this issue, we developed a dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction (PPI) between UBE2M and DCN1─which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs)─and histone deacetylase (HDAC) activity. Inspired by the synergistic antitumor effects observed with combined inhibition of UBE2M-DCN1 and HDAC, we designed hybrid molecules integrating pharmacophores targeting both pathways. Our preferred compound JN210 effectively disrupts the UBE2M-DCN1 interaction and inhibits HDAC, demonstrating significantly enhanced cytotoxicity compared to the parent compounds in vitro and potent tumor growth suppression in vivo. Mechanistic studies revealed dual blockade of CRL neddylation and induction of histone hyperacetylation, resulting in impaired DNA damage repair and synergistic apoptosis. As a novel DCN1/HDAC dual inhibitor, JN210 represents a promising therapeutic candidate for NSCLC.
Tao Zheng, Yigui Li, Yunyuan Huang et al.· Journal of Medicinal Chemist...· 0 citations
The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.
Yuzhan Li, Yaxun Guo, Dazhao Mi et al.· European journal of medicina...· 0 citations
Cell-based assays showed that SA13 can mediate the internalization of PD-L1 and strongly block hPD-1 and hPD-L1 interaction, demonstrating its effectiveness in biological events and indicating that SA13 is a promising and safe novel antitumor agent worthy of further development.
Jianwei Wang, Shenwei Yu, Liang Qian et al.· Journal of Medicinal Chemist...· 0 citations
The Forkhead box M1 (FoxM1) transcription factor is a well-established oncogenic driver, with its overexpression closely associated with tumor grade, aggressiveness and adverse clinico-pathological features across multiple cancer types. This has garnered considerable therapeutic interest in FoxM1 as a potential target. However, current FoxM1 inhibition strategies suffer from significant limitations or lack clinical validation. In the present study, we employed a structure based rational drug design approach to screen small molecule inhibitors targeting the FoxM1-DNA binding domain (FoxM1-DBD) using the NCI compound library. Selected lead compounds exhibited potent suppression of FoxM1and its targets in CaSki cervical cancer cells, outperforming conventional FoxM1 inhibitors. Electrophoretic Mobility Shift Assay (EMSA) and tryptophan specific fluorescence analyses confirmed direct and specific interaction of the compounds with FoxM1, resulting in effective disruption of FoxM1-DNA binding. Functional characterization revealed that these inhibitors robustly induced apoptosis as evidenced by enhanced PARP and caspase-7 cleavage. Furthermore, the lead compounds demonstrated activity across multiple cancer cell types and markedly attenuated key malignant traits of cancer cells, including proliferation, anchorage-independent growth, migration and invasion. Importantly, FoxM1 knockdown significantly diminished the tumor suppressive effects of the lead compounds thereby affirming target specificity. Collectively, our findings identify novel and selective small molecule inhibitors of FoxM1 that effectively disrupt FoxM1-driven oncogenic programs, highlighting their strong potential to evolve into credible anti-cancer therapeutics.
P. Cheema, N. Jaiswal, Sanjay Kumar Dey et al.· Biochimica et biophysica act...· 0 citations