Discovery of new benzhydrol biscarbonate esters as potent and selective apoptosis inducers of human melanomas bearing the activated ERK pathway: SAR studies on an ERK MAPK signaling modulator, ACA-28

  • Bioorg Chem. 2020 Oct;103:104137. doi: 10.1016/j.bioorg.2020.104137.
Ryosuke Satoh  1 ,  Naoya Hamada  2 ,  Ami Yamada  3 ,  Yuki Kanda  4 ,  Fumihiro Ishikawa  5 ,  Teruaki Takasaki  6 ,  Genzoh Tanabe  7 ,  Reiko Sugiura  8
Affiliations
  • 1. Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 2. Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 3. Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 4. Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 5. Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 6. Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 7. Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
  • 8. Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: [email protected].
PMID: 32763519 DOI: 10.1016/j.bioorg.2020.104137
Abstract

The recent discovery that an ERK signaling modulator [ACA-28 (2a)] preferentially kills human melanoma cell lines by inducing ERK-dependent Apoptosis has generated significant interest in the field of anti-cancer therapy. In the first SAR study on 2a, here, we successfully developed candidates (2b, 2c) both of which induce more potent and selective Apoptosis towards ERK-active melanoma cells than 2a, thus revealing the structural basis for inducing the ERK-dependent Apoptosis and proposing the therapeutic prospect of these candidates against ERK-dependent cancers represented by melanoma.

Keywords
ACA-28; Anti-melanoma activity; Apoptosis; Benzhydrol derivatives; ERK MAPK; SAR Study.
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