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

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 EGFRWT and Her4 enzymes in the radioisotope filter binding assay. The lead (4, SAB402) displayed potent dual biochemical activities with EGFRWT/Her4 IC50 ratio of 80 due to its potent inhibition of Her4 activity (IC50 0.03 nM), however, the selectivity towards activating mutations (EGFRL858R, EGFRex19del) 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.

journal_name

Bioorg Med Chem Lett

authors

Mansour TS,Pallepati RR,Basetti V

doi

10.1016/j.bmcl.2020.127288

subject

Has Abstract

pub_date

2020-08-15 00:00:00

pages

127288

issue

16

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30398-X

journal_volume

30

pub_type

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