Tetrahydroquinoline/4,5-Dihydroisoxazole Molecular Hybrids as Inhibitors of Breast Cancer Resistance Protein (BCRP/ABCG2).

Abstract

Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P-glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2-specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5-dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate-sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5-dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors.

• Authors: Luis C Vesga, Thales Kronenberger, Arun Kumar Tonduru, Diogo Henrique Kita, Ingrid Fatima Zattoni, Cristian Camilo Bernal, Arnold R Romero Bohórquez, Stelia Carolina Mendez-Sánchez, Suresh V Ambudkar, Glaucio Valdameri, Antti Poso
• Journal: ChemMedChem (ChemMedChem) Vol. 16 Issue 17 Pg. 2686-2694 (09 06 2021) ISSN: 1860-7187 [Electronic] Germany
• PMID: 33844464 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Isoxazoles
• Neoplasm Proteins
• Quinolines
• 1,2,3,4-tetrahydroquinoline

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Isoxazoles (chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Quinolines (chemistry, pharmacology)
• Structure-Activity Relationship