Design and synthesis of diphenylpyrimidine derivatives (DPPYs) as potential dual EGFR T790M and FAK inhibitors against a diverse range of cancer cell lines

  • Bioorg Chem. 2020 Jan:94:103408. doi: 10.1016/j.bioorg.2019.103408.
Min Ai  1 ,  Changyuan Wang  1 ,  Zeyao Tang  1 ,  Kexin Liu  1 ,  Xiuli Sun  2 ,  Tengyue Ma  3 ,  Yanxia Li  2 ,  Xiaodong Ma  1 ,  Lei Li  4 ,  Lixue Chen  5
Affiliations
  • 1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
  • 2. Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
  • 3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China.
  • 4. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: [email protected].
  • 5. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: [email protected].
PMID: 31706682 DOI: 10.1016/j.bioorg.2019.103408
Abstract

A new class of pyrimidine derivatives were designed and synthesized as potential dual FAK and EGFRT790M inhibitors using a fragment-based drug design strategy. This effort led to the identification of the two most active inhibitors, namely 9a and 9f, against both FAK (IC50 = 1.03 and 3.05 nM, respectively) and EGFRT790M (IC50 = 3.89 and 7.13 nM, respectively) kinase activity. Moreover, most of these compounds also exhibited strong antiproliferative activity against the three evaluated FAK-overexpressing pancreatic Cancer (PC) cells (AsPC-1, BxPC-3, Panc-1) and two drug-resistant Cancer cell lines (breast Cancer MCF-7/adr cells and lung Cancer H1975 cells) at concentrations lower than 6.936 μM. In addition, 9a was also effective in the in vivo assessment conducted in a FAK-driven human AsPC-1 cell xenograft mouse model. Overall, this study offers a new insight into the treatment of hard to treat cancers.

Keywords
Dual-target; EGFR T790M; FAK; Fragment-based drug design; Inhibitor.
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