Potent dual EGFR/Her4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides

Tarek S Mansour; Ranga R Pallepati; Vishnu Basetti

doi:10.1016/j.bmcl.2020.127288

Potent dual EGFR/Her4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127288. doi: 10.1016/j.bmcl.2020.127288. Epub 2020 May 28.

Authors

Tarek S Mansour¹, Ranga R Pallepati², Vishnu Basetti²

Affiliations

¹ Sabila Biosciences LLC, 5 Overlook Road, New City, NY 10956 USA. Electronic address: tsmansour@sabilabiosciences.com.
² Aurigene Discovery Technology Ltd. Bollaram Road, Miyapur, Hyderabad, 500 049 Telangana, India.

PMID: 32631510
DOI: 10.1016/j.bmcl.2020.127288

Abstract

Modifications at C₆ and C₇ positions of 3-cyanoquinolines 6 and 7 led to potent inhibitors of the ErbB family of kinases particularly against EGFR^WT and Her4 enzymes in the radioisotope filter binding assay. The lead (4, SAB402) displayed potent dual biochemical activities with EGFR^WT/Her4 IC₅₀ ratio of 80 due to its potent inhibition of Her4 activity (IC₅₀ 0.03 nM), however, the selectivity towards activating mutations (EGFR^L858R, EGFR^ex19del) was decreased. Inhibitor 4 also exhibited excellent growth inhibition in seven different cancer types and reduced cell viability in female NMRI nude mice in the intraperitoneally implanted hollow fibers which have been loaded with MOLT-4 (leukemia) and NCI-H460 (NSCLC) cells in a statistically significant manner.

Keywords: 2-(1,2-dithiolan-4-yl)acetic acid; Cyanoquinolines; EGFR; Glycerol; H460; Her4; Hollow fiber assay; Homoasparagusic acid; MOLT4; NCI-60.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, ErbB-4 / antagonists & inhibitors*
Receptor, ErbB-4 / metabolism
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*

Substances

Acetamides
Protein Kinase Inhibitors
Sulfhydryl Compounds
EGFR protein, human
ERBB4 protein, human
ErbB Receptors
Receptor, ErbB-4