Discovery of the Triazolo[1,5-a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance

Abstract

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo­[1,5-a]­pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo­[1,5-a]­pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

“…[ 1 ] P‐gp is a key membrane transporter involved in MDR by increasing efflux of drugs in cells and reducing drug intake, which is a major obstacle to cancer chemotherapy. [ 2‐5 ] The combinations of anticancer drugs and MDR reversing agents, such as P‐gp inhibitors, become the ideal choices to overcome MDR in cancer treatment aiming for the higher success rates of chemotherapy. [ 6‐7 ] The development of effective MDR reversing agents to restore the sensitivity of cancer cells to the anticancer drugs is thus critical for chemotherapy.…”

Simplified Derivatives of Tetrandrine as Potent and Specific P-gp Inhibitors to Reverse Multidrug Resistance in Cancer Chemotherapy

“…Accordingly, once the efflux function is inhibited, intracellular accumulation of anticancer drugs will be restored to the effective therapeutic concentrations to kill cancer cells. Therefore, discovery of potent P-gp inhibitors to co-administrate with traditional chemotherapeutic drugs has long been recognized as a very promising strategy for reversing MDR in clinic. − …”

Imidazo[1,2-a]Pyridine Derivatives as Novel Dual-Target Inhibitors of ABCB1 and ABCG2 for Reversing Multidrug Resistance

“…The past few decades of research demonstrates that MDR tumor cells attenuate the efficacy of anticancer drugs through drug efflux mediated by ATP-binding cassette (ABC) transporters. ,− These ABC transporters are thus the ideal therapeutic target to overcome MDR. Two major human ABC transporters, including ABCB1 (P-glycoprotein, P-gp) and ABCG2 (breast cancer resistance protein, BCRP), are drug efflux transporters with ATP-binding regions to play a key role in the clinical development of MDR. − These proteins pump chemotherapy drugs out of cells in an active transport manner, thus reducing intracellular drug levels. , ABCB1 is the most studied ABC transporter in clinical research, and its inhibitors have been developed across three generations, such as verapamil (VRP, first generation), dexverapamil (second generation), and tariquidar (third generation) (Figure A). − The first-generation ABCB1 inhibitors are acquired from drugs in clinical research used for other diseases (e.g., hypertension, rheumatoid arthritis, and malignant tumor) but failed in clinical trials due to the serious toxicity. − The second-generation inhibitors, which are mainly derived from the first-generation inhibitors, show higher selectivity and lower toxicity . However, results of clinical trials were not satisfactory.…”