2. Academic Validation
  3. Ligand-based optimization and biological evaluation of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide derivatives as potent intrinsically disordered protein c-Myc inhibitors

Ligand-based optimization and biological evaluation of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide derivatives as potent intrinsically disordered protein c-Myc inhibitors

  • Bioorg Med Chem Lett. 2021 Jan 1:31:127711. doi: 10.1016/j.bmcl.2020.127711.
Limin Chen 1,  Beiming Cheng 1,  Qi Sun 2,  Luhua Lai 3
Affiliations

Affiliations

  • 1 Peking-Tsinghua Center for Life Sciences at Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 2 BNLMS, Peking-Tsinghua Center for Life Sciences at the College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address: xiaoqi45@126.com.
  • 3 Peking-Tsinghua Center for Life Sciences at Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; BNLMS, Peking-Tsinghua Center for Life Sciences at the College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: lhlai@pku.edu.cn.
PMID: 33246106 DOI: 10.1016/j.bmcl.2020.127711
Abstract

The transcription factor c-Myc is a well-known onco-protein and an intrinsically disordered protein (IDP). As its aberrant expression is frequently observed in various human cancers, c-Myc is considered as a key drug target. However, due to its high conformational flexibility, directly targeting c-Myc remains difficult. Here we explored the structure-activity relationships (SAR) of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide compounds and reported sixteen novel active compounds. Among them, compound PKUMDL-CLM-32 (hereafter, 32) showed the best anti-proliferation activity in cells with an EC50 of 3.3 μM. We demonstrated that 32 directly disrupts c-Myc/Max interaction and induces the degradation of c-Myc protein in cells. We showed that 32 induces cell cycle arrest at S phase and promotes Apoptosis of HL-60 cells. This study provides an example of using ligand-based analysis to optimize IDP ligands.

Keywords

Intrinsically disordered protein; Protein degradation; Structure-activity relationships; c-Myc.

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