Discovery of carbazole derivatives as novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening

Dandan Xi; Yan Niu; Hongyue Li; Stefan M Noha; Veronika Temml; Daniela Schuster; Chao Wang; Fengrong Xu; Ping Xu

doi:10.1016/j.ejmech.2019.06.027

Discovery of carbazole derivatives as novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening

Eur J Med Chem. 2019 Sep 15:178:802-817. doi: 10.1016/j.ejmech.2019.06.027. Epub 2019 Jun 15.

Authors

Dandan Xi¹, Yan Niu², Hongyue Li¹, Stefan M Noha³, Veronika Temml³, Daniela Schuster⁴, Chao Wang¹, Fengrong Xu¹, Ping Xu⁵

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
² Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China. Electronic address: yanniu@bjmu.edu.cn.
³ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria.
⁴ Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria; Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University Salzburg, Strubergasse 21, 5020, Salzburg, Austria. Electronic address: daniela.schuster@uibk.ac.at.
⁵ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China. Electronic address: pingxu@bjmu.edu.cn.

PMID: 31252285
DOI: 10.1016/j.ejmech.2019.06.027

Abstract

We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC₅₀ = 27.2 ± 4.5 μM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC₅₀ = 12.8 ± 0.5 μM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC₅₀ > 100 μM) than M100 (IC₅₀ = 8.9 ± 2.0 μM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.

Keywords: Bioisosterism; Carbazoles; MEK inhibitor; Pharmacophore modeling; Virtual screening.

MeSH terms

Allosteric Regulation / drug effects
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbazoles / chemical synthesis
Carbazoles / chemistry
Carbazoles / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
HEK293 Cells
Humans
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbazoles
Protein Kinase Inhibitors
carbazole
MAP Kinase Kinase Kinases

Grants and funding

T 942/FWF_/Austrian Science Fund FWF/Austria