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  3. Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives

Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives

  • Bioorg Med Chem. 2016 Aug 15;24(16):3501-12. doi: 10.1016/j.bmc.2016.05.063.
Samar Mowafy 1,  A Galanis 2,  Zainab M Doctor 3,  Raymond M Paranal 2,  Deena S Lasheen 4,  Nahla A Farag 5,  Pasi A Jänne 2,  Khaled A M Abouzid 6
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., SGM 628, Boston, MA 02115, USA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District) Cairo, Egypt. Electronic address: samarmowafy@gmail.com.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., SGM 628, Boston, MA 02115, USA.
  • 4 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566 Cairo, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District) Cairo, Egypt.
  • 6 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566 Cairo, Egypt. Electronic address: khaled.abouzid@pharma.asu.edu.eg.
PMID: 27288180 DOI: 10.1016/j.bmc.2016.05.063
Abstract

A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495-9.05nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC50=1.76-2.38μM) in these mutant lines and significant Her2 Enzyme inhibition (IC50=19.2-40.6nM) compared to lapatinib (60.1nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure-activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR.

Keywords

EGFR Del19/T790M mutant; EGFR L858R/T790 mutant; EGFR inhibitors; EGFR-Her2 dual inhibitors; Quinazolines; Synthesis; Urea derivatives.

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