2. Academic Validation
  3. Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors

Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors

  • Bioorg Med Chem. 2016 Jul 1;24(13):3083-3092. doi: 10.1016/j.bmc.2016.05.025.
Sheng-Biao Wang 1,  Mu-Tian Cui 1,  Xiao-Feng Wang 2,  Emika Ohkoshi 3,  Masuo Goto 3,  De-Xuan Yang 4,  Linna Li 4,  Shoujun Yuan 4,  Susan L Morris-Natschke 3,  Kuo-Hsiung Lee 5,  Lan Xie 6
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
  • 2 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Pharmacy Department, Urumqi General Hospital, Lanzhou Military Region, Urumqi 830000, China.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
  • 4 Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China.
  • 5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University & Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
  • 6 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA. Electronic address: lanxie4@gmail.com.
PMID: 27238842 DOI: 10.1016/j.bmc.2016.05.025
Abstract

Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4-7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54μM), as well as Other human tumor cell lines (GI50<20μM), and a desirable druglike property profile with low logP value (2.54) and high aqueous solubility (95.6μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound.

Keywords

4-Substituted 2-phenylaminoquinazolines; Antiproliferative; Mer tyrosine kinase inhibitors; Molecular modeling; Physicochemical properties.

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