The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP

Abstract

ATP-binding cassette (ABC) transporters, such as breast cancer resistance protein (BCRP), are key players in resistance to multiple anti-cancer drugs, leading to cancer treatment failure and cancer-related death. Currently, there are no clinically approved drugs for reversal of cancer drug resistance caused by ABC transporters. This study investigated if a novel drug candidate, SCO-201, could inhibit BCRP and reverse BCRP-mediated drug resistance. We applied in vitro cell viability assays in SN-38 (7-Ethyl-10-hydroxycamptothecin)-resistant colon cancer cells and in non-cancer cells with ectopic expression of BCRP. SCO-201 reversed resistance to SN-38 (active metabolite of irinotecan) in both model systems. Dye efflux assays, bidirectional transport assays, and ATPase assays demonstrated that SCO-201 inhibits BCRP. In silico interaction analyses supported the ATPase assay data and suggest that SCO-201 competes with SN-38 for the BCRP drug-binding site. To analyze for inhibition of other transporters or cytochrome P450 (CYP) enzymes, we performed enzyme and transporter assays by in vitro drug metabolism and pharmacokinetics studies, which demonstrated that SCO-201 selectively inhibited BCRP and neither inhibited nor induced CYPs. We conclude that SCO-201 is a specific, potent, and potentially non-toxic drug candidate for the reversal of BCRP-mediated resistance in cancer cells.

An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial

“…An interesting point is that the function of ABCG2 can be inhibited in patients [11]. In Scandion Oncology, we develop novel drugs to inhibit ABCG2 [12,13]. When these drugs have been tested in regular clinical phase II trials in patients with metastatic and irinotecan resistant colorectal cancer, they can be taken into randomized clinical testing including Stage III colon cancer patients with high ABCG2 expression.…”

Anticancer Potential of Compounds from the Brazilian Blue Amazon

“…Fumitremorgin C (▶ Fig. 9) is an indolyl diketopiperazine alkaloid that was the first identified inhibitor of BCRP [135]. The BCRP, also named ABCG2, is a membrane protein half-molecule ABC transporter, responsible for pumping out a wide range of chemotherapeutic agents and, thus, it functions as a key player in the multidrug-resistance phenotype of cancer cells.…”

“…Fumitremorgin C reversed chemoresistance to distinct chemotherapeutic agents including mitoxantrone, topotecan, and doxorubicin in colon cancer [136] and almost completely reversed the chemoresistance to mitoxantrone in breast cancer that overexpresses BCRP [137]. However, despite its elevated inhibitory potency, its clinical use was abolished due to neurotoxic side effects [135].…”

BMS-599626, a Highly Selective Pan-HER Kinase Inhibitor, Antagonizes ABCG2-Mediated Drug Resistance

“…There are 49 ABC transporters, divided into subfamilies from A to G [ 2 ]. ABCG2, also known as breast cancer resistance protein (BCRP) and mitoxantrone resistance (MXR) transporter, is one of these 49 transporters, and remains one of the most extensively studied transporters [ 18 , 19 ]. It is a 72 kDa protein with the highest concentrations in the brain, kidneys, intestines, placenta, and colon.…”