Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line MDA-MB-468

Jeyun Jo; Sou Hyun Kim; Heegyu Kim; Myeonggyo Jeong; Jae-Hwan Kwak; Young Taek Han; Jee-Yeong Jeong; Young-Suk Jung; Hwayoung Yun

doi:10.1016/j.bmcl.2018.11.010

Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line MDA-MB-468

Bioorg Med Chem Lett. 2019 Jan 1;29(1):62-65. doi: 10.1016/j.bmcl.2018.11.010. Epub 2018 Nov 8.

Authors

Jeyun Jo¹, Sou Hyun Kim¹, Heegyu Kim¹, Myeonggyo Jeong¹, Jae-Hwan Kwak², Young Taek Han³, Jee-Yeong Jeong⁴, Young-Suk Jung⁵, Hwayoung Yun⁶

Affiliations

¹ College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
² College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea.
³ College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea.
⁴ Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
⁵ College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea. Electronic address: [email protected].
⁶ College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea. Electronic address: [email protected].

PMID: 30447889
DOI: 10.1016/j.bmcl.2018.11.010

Abstract

Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been considered to be an important target for TNBC therapy, but efficacies of EGFR inhibitors in clinical trials are elusive. In this study, novel series of 2-anilinopyrimidines were synthesized in an effort to identify selective inhibitors against an EGFR-overexpressing TNBC cell line. Biological evaluation demonstrated that compounds 21 and 38, with a 4-methylpiperidine group and a high ClogP value, exhibited good potency and selectivity for the TNBC cell line. This study has provided evidence to support further development of 2-anilinopyrimidine-based TNBC selective inhibitors and investigation of the targets of compounds 21 and 38.

Keywords: 2-Anilinopyrimidine; Growth inhibition; Lipophilicity; Selectivity index; Triple-negative breast cancer.

Publication types

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

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / 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 Discovery*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
MCF-7 Cells
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
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology

Substances

Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
EGFR protein, human
ErbB Receptors