2. Academic Validation
  3. Discovery of benzimidazole-based Mcl-1 inhibitors via AlphaShape-enabled virtual screening

Discovery of benzimidazole-based Mcl-1 inhibitors via AlphaShape-enabled virtual screening

  • Eur J Med Chem. 2026 Jan 5:301:118229. doi: 10.1016/j.ejmech.2025.118229.
Yiming Nie 1,  Jintong Du 2,  Xin Yan 3,  Haihan Liu 1,  Jiaqi Liu 1,  Hu Ge 4,  Hao Fang 5,  Xuben Hou 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Phase I Clinical Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
  • 3 WeCompute Science, Shanghai, 201203, China.
  • 4 WeCompute Science, Shanghai, 201203, China. Electronic address: geh@wecomput.com.
  • 5 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: haofangcn@sdu.edu.cn.
  • 6 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: hxb@sdu.edu.cn.
PMID: 41075605 DOI: 10.1016/j.ejmech.2025.118229
Abstract

As an essential regulator of tumor cell survival mechanisms, myeloid cell leukemia 1 (Mcl-1) represents a promising anti-cancer target. This study describes the identification of novel benzimidazole scaffolds targeting Mcl-1 through AlphaShape, a deep neural network-empowered shape-based screening program. Through structure-based optimization of the initial hit compound, we developed a series of derivatives exhibiting enhanced binding specificity for Mcl-1 over Bcl-2/Bcl-xL. Notably, compounds 26c and 26d demonstrated submicromolar binding affinities (Ki = 0.59 and 0.74 μM, respectively) with concomitant antiproliferative effects in pancreatic Cancer cells through Apoptosis induction. Furthermore, the binding mode of 26d was elucidated through an integrated approach combining molecular dynamics simulation and HSQC-NMR spectroscopy. Our findings not only validate AlphaShape as an efficient tool for lead discovery but also provide a strategic framework for developing targeted Mcl-1 inhibitors with therapeutic potential in pancreatic Cancer treatment.

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