1. Academic Validation
  2. A BPTF Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Murine Triple-Negative Breast Cancer Cells to Chemotherapy

A BPTF Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Murine Triple-Negative Breast Cancer Cells to Chemotherapy

  • Int J Mol Sci. 2024 Oct 22;25(21):11346. doi: 10.3390/ijms252111346.
Melanie M Sinanian 1 Afshan Rahman 1 Ahmed M Elshazly 1 2 Victoria Neely 3 Balaji Nagarajan 4 Glen E Kellogg 4 April L Risinger 5 David A Gewirtz 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 3 Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • 4 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • 5 Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Abstract

Triple-negative breast Cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger-containing transcription factor), was capable of sensitizing preclinical models of TNBC to chemotherapy in part via the promotion of Autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with the inhibition of the P-glycoprotein (P-gp) efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump in a manner consistent with the inhibition of the pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in TNBC, that has not yet been successfully addressed by clinical efforts.

Keywords

AU1; BPTF inhibitor; P-glycoprotein; P-gp; breast cancer; efflux pump; multidrug resistance; multidrug resistance pump; triple-negative breast cancer.

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