Related Experiment Video
Updated: Aug 15, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Structure-Based Discovery of JN210 as a Potent Dual DCN1/HDAC Inhibitor for the Treatment of Nonsmall Cell Lung
Tao Zheng1,2, Yigui Li2, Yunyuan Huang3
1Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen529020, P. R. China.
Abstract:
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.
Insights
A novel dual-targeting therapy inhibits UBE2M-DCN1 protein interactions and histone deacetylase (HDAC) activity. This approach shows promise for treating nonsmall cell lung cancer (NSCLC) by enhancing cytotoxicity and suppressing tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Nonsmall cell lung cancer (NSCLC) treatment faces challenges due to resistance to monotherapy.
- Targeting oncogenic protein-protein interactions (PPIs) and epigenetic modifiers like histone deacetylases (HDACs) offers potential therapeutic avenues.
Purpose of the Study:
- To develop a dual-targeting strategy inhibiting both the UBE2M-DCN1 PPI and HDAC activity for NSCLC treatment.
- To evaluate the efficacy of a novel dual inhibitor, JN210, in preclinical NSCLC models.
Main Methods:
- Design and synthesis of hybrid molecules targeting UBE2M-DCN1 interaction and HDAC activity.
- In vitro cytotoxicity assays and in vivo tumor growth suppression studies.
- Mechanistic investigations into CRL neddylation, histone acetylation, DNA damage repair, and apoptosis.
Main Results:
- Compound JN210 effectively inhibited UBE2M-DCN1 interaction and HDAC activity.
- JN210 demonstrated superior cytotoxicity and tumor growth inhibition compared to parent compounds.
- Dual inhibition led to CRL neddylation blockade, histone hyperacetylation, impaired DNA repair, and synergistic apoptosis.
Conclusions:
- JN210 acts as a novel DCN1/HDAC dual inhibitor.
- The dual-targeting strategy shows significant therapeutic potential for NSCLC.
- JN210 represents a promising candidate for further NSCLC drug development.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:23Abnormal Proliferation
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...