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Development of thiazole-valine peptidomimetic as modulators of human multidrug transporter P-glycoprotein

Wednesday, September 14, 2016 — Poster Session I

3:00 p.m. – 4:30 p.m.
FAES Terrace


  • B Abel
  • B Patel
  • T Talele*
  • SV Ambudkar*


P-glycoprotein (P-gp, ABCB1) is a member of the superfamily of ATP-binding cassette (ABC) proteins, that utilizes energy from ATP hydrolysis to efflux a variety of hydrophobic and amphipathic compounds including anticancer drugs. P-gp plays an important role in the development of resistance to anticancer drugs in cancer patients resulting in failure of chemotherapy. One of our goals is to develop non-toxic potent modulators of P-gp and other ABC drug transporters to overcome drug resistance in cancer cells. In this study, 45 novel compounds were synthesized by peptide coupling at corresponding carboxyl and amino termini of (S)-valine based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. To evaluate the interaction of (S)-valine based derivatives at the drug-binding pocket of P-gp, biochemical assays including photolabeling with [125I]-Iodoarylazidoprazosin and ATP hydrolysis were employed. We found that compounds carrying the 2-aminobenzophenone group at the carboxyl terminus of the monothiazole derivatives stimulate the basal ATPase activity of P-gp. On the other hand, replacing the 2-aminobenzophenone group on the carboxyl terminus with difluoro-cyclohexane group in BTT-25 resulted in 33% inhibition of the basal ATPase activity at lower concentrations. To assess the interaction of BTT compounds at the drug-binding pocket of P-gp, photolabeling of P-gp with [125I]-IAAP was also determined. BTT 25 compound inhibited photolabeling of P-gp with 125IAAP at nanomolar concentrations (IC50 = 0.1 µM). Based on these results, we propose that further chemical modification of BTT 25 compound could lead to the development of non-toxic modulator to overcome P-gp-mediated resistance to anticancer drugs.

Category: Cancer Biology