2. Academic Validation
  3. Structure-Based Optimization of 3-Phenyl- N-(2-(3-phenylureido)ethyl)thiophene-2-sulfonamide Derivatives as Selective Mcl-1 Inhibitors

Structure-Based Optimization of 3-Phenyl- N-(2-(3-phenylureido)ethyl)thiophene-2-sulfonamide Derivatives as Selective Mcl-1 Inhibitors

  • J Med Chem. 2021 Jul 22;64(14):10260-10285. doi: 10.1021/acs.jmedchem.1c00690.
Yan Li 1 2,  Wenjie Fan 2,  Qineng Gong 1,  Jie Tian 2,  Mi Zhou 1,  Qing Li 2,  Laura B Uwituze 3,  Zhichao Zhang 3,  Ran Hong 4,  Renxiao Wang 1 2 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
  • 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China.
  • 3 State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, People's Republic of China.
  • 4 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China.
  • 5 Shanxi Key Laboratory of Innovative Drugs for the Treatment of Serious Diseases Basing on Chronic Inflammation, College of Traditional Chinese Medicines, Shanxi University of Chinese Medicine, Taiyuan, Shanxi 030619, People's Republic of China.
PMID: 34228434 DOI: 10.1021/acs.jmedchem.1c00690
Abstract

Selective Mcl-1 inhibitors may overcome the drug resistance caused by current anti-apoptotic Bcl-2 protein inhibitors in tumors with Mcl-1 overexpression. Based on previously discovered compounds with a 3-phenylthiophene-2-sulfonamide core moiety, in this work, we have obtained new compounds with improved binding affinity and/or selectivity under the guidance of structure-based design. The most potent compounds achieved sub-micromolar binding affinities to Mcl-1 (Ki ∼ 0.4 μM) and good cytotoxicity (IC50 < 10 μM) on several tumor cells. 15N-heteronuclear single-quantum coherence NMR spectra suggested that these compounds bound to the BH3-binding groove on Mcl-1. Several cellular assays revealed that FWJ-D4 as well as its precursor FWJ-D5 effectively induced caspase-dependent Apoptosis, and their target engagement at Mcl-1 was confirmed by co-immunoprecipitation experiments. Treatment with FWJ-D5 at 50 mg/kg every 2 days on an RS4;11 xenograft mouse model for 22 days led to 75% reduction in tumor volume without body weight loss.

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