Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer

Feng Gao; Xiaoxu Chen; Junyan Lu; Shulei Hu; Hui Xu; Yuqiang Shi; Mingshun Feng; Jian Ding; Hong Liu; Cheng Luo; Zuoquan Xie; Jiang Wang

doi:10.1016/j.ejmech.2021.113274

Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer

Eur J Med Chem. 2021 Apr 5:215:113274. doi: 10.1016/j.ejmech.2021.113274. Epub 2021 Feb 7.

Authors

Feng Gao¹, Xiaoxu Chen², Junyan Lu¹, Shulei Hu¹, Hui Xu¹, Yuqiang Shi¹, Mingshun Feng³, Jian Ding², Hong Liu², Cheng Luo⁴, Zuoquan Xie⁵, Jiang Wang⁶

Affiliations

¹ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
³ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
⁴ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: cluo@simm.ac.cn.
⁵ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zqxie@simm.ac.cn.
⁶ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: jwang@simm.ac.cn.

PMID: 33592537
DOI: 10.1016/j.ejmech.2021.113274

Abstract

Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC₅₀ ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo.

Keywords: AKT inhibitor; Ceramide analogs; Colon cancer; Combination therapy; MK2206.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Ceramides / chemical synthesis
Ceramides / pharmacokinetics
Ceramides / therapeutic use*
Drug Design
Drug Synergism
Female
G1 Phase Cell Cycle Checkpoints / drug effects
Heterocyclic Compounds, 3-Ring / therapeutic use*
Humans
Mice
Mice, Inbred BALB C
Naphthalenes / chemical synthesis
Naphthalenes / pharmacokinetics
Naphthalenes / therapeutic use
Neoplasms / drug therapy*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents
Ceramides
Heterocyclic Compounds, 3-Ring
MK 2206
Naphthalenes
Protein Kinase Inhibitors
Reactive Oxygen Species
Proto-Oncogene Proteins c-akt