Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation

Hong Chen; Feihong Chen; Sinan Pei; Shaohua Gou

doi:10.1016/j.bioorg.2019.03.035

Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation

Bioorg Chem. 2019 Jun:87:191-199. doi: 10.1016/j.bioorg.2019.03.035. Epub 2019 Mar 19.

Authors

Hong Chen¹, Feihong Chen¹, Sinan Pei¹, Shaohua Gou²

Affiliations

¹ Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
² Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China. Electronic address: [email protected].

PMID: 30901674
DOI: 10.1016/j.bioorg.2019.03.035

Abstract

As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in cancer therapy. Here we report several pomalidomide hybrids acting as proteolysis targeting chimeras (PROTACs) for the degradation of B-Raf. Due to its high expression of B-Raf, MCF-7 cells are sensitive to these compounds. Among them, compound 2 can effectively kill cancer cells via inducing cells apoptosis. As a B-Raf degrader, compound 2 can accelerate the degradation of B-Raf by recruiting ubiquitin-proteasome system, and further affects the expression of Mcl-1, a downstream protein of B-Raf. The anticancer mechanism of compound 2 is quite different from its mother compound and cancer cells seem to be more sensitive to the degrader, hinting that degradation of B-Raf by PROTAC is a potential way for cancer treatment.

Keywords: Anticancer activity; B-Raf; Pomalidomide; Proteolysis targeting chimeras.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
MCF-7 Cells
Molecular Structure
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proteolysis / drug effects*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Structure-Activity Relationship
Thalidomide / analogs & derivatives*
Thalidomide / chemical synthesis
Thalidomide / chemistry
Thalidomide / pharmacology

Substances

Antineoplastic Agents
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Protein Kinase Inhibitors
Thalidomide
pomalidomide
Proto-Oncogene Proteins B-raf