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

Ryosuke Satoh; Naoya Hamada; Ami Yamada; Yuki Kanda; Fumihiro Ishikawa; Teruaki Takasaki; Genzoh Tanabe; Reiko Sugiura

doi:10.1016/j.bioorg.2020.104137

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. Epub 2020 Jul 25.

Authors

Ryosuke Satoh¹, Naoya Hamada², Ami Yamada³, Yuki Kanda⁴, Fumihiro Ishikawa⁵, Teruaki Takasaki⁶, Genzoh Tanabe⁷, Reiko Sugiura⁸

Affiliations

¹ Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: satohr@phar.kindai.ac.jp.
² Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: 1933420001u@kindai.ac.jp.
³ Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: 1511610091j@kindai.ac.jp.
⁴ Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: 1745110004k@kindai.ac.jp.
⁵ Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: ishikawa@phar.kindai.ac.jp.
⁶ Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: takasaki@phar.kindai.ac.jp.
⁷ Laboratory of Organic Chemistry, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: g-tanabe@phar.kindai.ac.jp.
⁸ Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Kowakae 3-4-1, Higashiosaka City, Osaka 577-8502, Japan. Electronic address: sugiurar@phar.kindai.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzhydryl Compounds / chemical synthesis
Benzhydryl Compounds / chemistry
Benzhydryl Compounds / pharmacology*
Carbonates / chemical synthesis
Carbonates / chemistry
Carbonates / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Esters / chemical synthesis
Esters / chemistry
Esters / pharmacology*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
MAP Kinase Signaling System / drug effects
Melanoma / drug therapy*
Melanoma / metabolism
Melanoma / pathology
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Benzhydryl Compounds
Carbonates
Esters
Extracellular Signal-Regulated MAP Kinases
benzohydrol