Discovery of a Novel Tetrahydro-β-Carboline Mcl-1 Inhibitor with Antitumor Activity and Capability to Overcome Cisplatin Resistance

  • J Med Chem. 2026 May 14;69(9):10621-10646. doi: 10.1021/acs.jmedchem.5c03796.
Dong-Yuan Ning  1  2 ,  Ru-Yi Luo  1  2 ,  Li-Fang Cen  1 ,  Fang-Xin Wang  1 ,  Yang-Han Liu  1 ,  Yan-Cheng Liu  1 ,  Ya-Ni Huang  1 ,  Hong Liang  1 ,  Zhen-Feng Chen  1
Affiliations
  • 1. Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources (Guangxi), School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 2. Guangxi Key Laboratory of Sericulture Ecology and Applied Intelligent Technology, Guangxi Collaborative Innovation Center of Modern Sericulture and Silk, Guangxi College Key Laboratory of Exploitation and Utilization of Microbial and Botanical Resources, School of Chemistry and Bioengineering, Hechi University, Hechi 546300, Guangxi, China.
PMID: 42084733 DOI: 10.1021/acs.jmedchem.5c03796
Abstract

Targeting Mcl-1 is a promising antitumor strategy; however, no Mcl-1 inhibitors have been clinically approved, primarily due to their suboptimal drug-like properties and drug resistance rather than insufficient potency. Herein, we report the discovery of a novel tetrahydro-β-carboline (THBC)-derived Mcl-1 Inhibitor, N5, which was identified by integrating structural insights with structure-based drug design (SBDD). N5 possesses a simple, synthetically accessible structure while exhibiting high binding affinity and selectivity for Mcl-1. This compound demonstrated potent cellular on-target activity, favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and in vivo efficacy in Mcl-1-dependent ovarian Cancer xenograft models (A2780S). Notably, its hydrochloride (designated N5Y) exhibited even better antitumor efficacy as a single agent and the ability to overcome cisplatin resistance, producing significant synergistic effects in combination therapy. Collectively, N5 represents a promising lead compound for the development of clinically applicable Mcl-1 inhibitors, with the potential to address key challenges of efficacy, safety, and drug resistance.

Products