2. Academic Validation
  3. Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer

Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer

  • Eur J Med Chem. 2021 Jan 1;209:112866. doi: 10.1016/j.ejmech.2020.112866.
Md Ashraf-Uz-Zaman 1,  Sadisna Shahi 1,  Racheal Akwii 1,  Md Sanaullah Sajib 1,  Mohammad Jodeiri Farshbaf 2,  Raja Reddy Kallem 3,  William Putnam 3,  Wei Wang 4,  Ruiwen Zhang 4,  Karina Alvina 5,  Paul C Trippier 6,  Constantinos M Mikelis 1,  Nadezhda A German 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
  • 2 Department of Biological Sciences, Texas Tech University, Lubbock, TX, USA.
  • 3 Clinical Pharmacology & Experimental Therapeutics Center, Texas Tech University Health Sciences Center, Dallas, TX, USA.
  • 4 College of Pharmacy, University of Houston, Houston, TX, USA.
  • 5 Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Biological Sciences, Texas Tech University, Lubbock, TX, USA; Department of Neuroscience, University of Florida, Gainesville, FL, USA.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, USA.
  • 7 Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Electronic address: nadezhda.german@ttuhsc.edu.
PMID: 33039722 DOI: 10.1016/j.ejmech.2020.112866
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive type of Cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast Cancer.

Keywords

Blood-brain-barrier; FGFR1; In silico; Neurotoxicity; Synthesis; Triple-negative breast cancer.

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