Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines

Changyuan Wang; Si Li; Qiang Meng; Xiuli Sun; Hua Li; Xiaohong Shu; Huijun Sun; Kexin Liu; Zhihao Liu; Xiaodong Ma

doi:10.1016/j.bmc.2018.07.007

Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines

Bioorg Med Chem. 2018 Aug 7;26(14):4179-4186. doi: 10.1016/j.bmc.2018.07.007. Epub 2018 Jul 6.

Authors

Changyuan Wang¹, Si Li¹, Qiang Meng¹, Xiuli Sun², Hua Li¹, Xiaohong Shu¹, Huijun Sun¹, Kexin Liu¹, Zhihao Liu³, Xiaodong Ma⁴

Affiliations

¹ College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China.
² Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
³ College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: liuzhihao12399@126.com.
⁴ College of Pharmacy, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.

PMID: 30006143
DOI: 10.1016/j.bmc.2018.07.007

Abstract

A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC₅₀ of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma.

Publication types

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

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
Amino Acids / chemistry
Amino Acids / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Leukocytes, Mononuclear / drug effects
Lymphoma, B-Cell / drug therapy*
Lymphoma, B-Cell / metabolism
Lymphoma, B-Cell / pathology
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Amino Acids
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human