BCRP (breast cancer resistance protein)
BCRP/ABCG2 (breast cancer resistance protein / ATP-binding cassette sub-family G member 2). KS176 is a selective inhibitor of the BCRP multidrug transporter. It has IC₅₀ values of 0.59 μM in Pheo A assays and 1.39 μM in Hoechst 33342 assays. KS176 shows no inhibition of P-gp or MRP1. BCRP is an ATP-binding cassette transporter that mediates the efflux of various anticancer drugs, contributing to multidrug resistance in cancer cells.

KS176 is a novel potent and highly selective/specific inhibitor of the breast cancer resistance protein (BCRP) multidrug transporter with IC50 values of 0.59 and 1.39 μM in Pheo A and Hoechst 33342 assays respectively. It displays no inhibitory activity against P-gp or MRP1. KS176 and its analogs share a noncompetitive-type interaction with pheophorbide A. Experiments with imatinib and pheophorbide A revealed a mixed-type interaction. This class of specific breast cancer resistance protein (BCRP) inhibitors showed no inhibition of the ATP binding cassette (ABC) transporters P-gp and MRP1. Some of these modulators inhibit BCRP with high potency; they are only slightly less potent than Ko143 and could serve as promising lead structures for the design of novel effective BCRP inhibitors. These inhibitors are structurally related to tariquidar (XR9576) and belong to a library of multidrug-resistance modulators
Kinase Assay: KS176 is a novel potent and highly selective/specific inhibitor of the breast cancer resistance protein (BCRP) multidrug transporter with IC50 values of 0.59 and 1.39 μM in Pheo A and Hoechst 33342 assays respectively.
Cell Assay:
In vitro, KS176 inhibits BCRP with IC₅₀ values of 0.59 μM in Pheo A assays and 1.39 μM in Hoechst 33342 assays. It has no inhibitory activity against P-gp or MRP1. The compound's selectivity for BCRP over other drug transporters makes it a valuable tool for studying BCRP function and for overcoming multidrug resistance in cancer.

Detailed in vivo activity data for KS176 are limited in publicly available sources. As a BCRP inhibitor, KS176 is expected to enhance the efficacy of anticancer drugs that are substrates of BCRP in vivo. The compound's selectivity for BCRP suggests that it could be used to overcome multidrug resistance in cancer therapy.

A new class of specific breast cancer resistance protein (BCRP) inhibitors was identified, showing no inhibition of the ATP binding cassette (ABC) transporters P-gp and MRP1. Some of these modulators inhibit BCRP with high potency; they are only slightly less potent than Ko143 and could serve as promising lead structures for the design of novel effective BCRP inhibitors. These inhibitors are structurally related to tariquidar (XR9576) and belong to a library of multidrug-resistance modulators synthesized by our research group. The absence of the tetrahydroisoquinoline substructure appears to play a crucial role for specificity; we found that the presence of this substructure is not essential for interaction with BCRP. To determine the type of interaction between pheophorbide A and compounds with and without the tetrahydroisoquinoline substructure, various substrate pheophorbide A concentrations were used in enzyme kinetics assays. The resulting data show that these compounds share a noncompetitive-type interaction with pheophorbide A. Experiments with imatinib and pheophorbide A revealed a mixed-type interaction. The combination of imatinib and compounds with and without the tetrahydroisoquinoline substructure resulted in a positive cooperative effect, indicating that imatinib engages a binding site distinct from that of the new compounds on one side and distinct from that of pheophorbide A on the other side as well. The results of this study suggest that the category of BCRP-specific inhibitors, which includes only fumitremorgin C, Ko143 and analogues, and novobiocin needs to be extended by this new class of inhibitors, which possess three key characteristics: specificity, potency, and low toxicity[1].
The BCRP inhibition assay for KS176 typically involves membrane vesicles from cells overexpressing BCRP or using cells expressing BCRP. For Pheo A assays, cells are loaded with the fluorescent BCRP substrate pheophorbide A and treated with varying concentrations of KS176. BCRP-mediated efflux is measured by intracellular fluorescence accumulation. For Hoechst 33342 assays, cells are loaded with Hoechst 33342, and efflux is measured. IC₅₀ values are calculated from dose-response curves.

Cells overexpressing BCRP (e.g., BCRP-transfected cell lines or drug-resistant cancer cell lines) are cultured in appropriate medium. Cells are treated with varying concentrations of KS176 (typically ranging from 0.1 to 100 μM) and loaded with fluorescent BCRP substrates (pheophorbide A or Hoechst 33342). Intracellular fluorescence is measured by flow cytometry or fluorescence plate reader. BCRP inhibition is assessed by increased intracellular fluorescence.

In vivo efficacy studies for KS176 likely involve mouse xenograft models of cancer where BCRP contributes to drug resistance. Immunodeficient mice are engrafted with BCRP-overexpressing tumor cells. When tumors are established, KS176 is administered in combination with a BCRP substrate anticancer drug. Tumor volumes are measured, and drug accumulation in tumors is assessed.

KS176 has a molecular weight of 405.4 g/mol and a molecular formula of C₂₂H₁₉N₃O₅. Detailed pharmacokinetic parameters are not extensively published. As a small molecule, KS176 is expected to be orally bioavailable. The compound is typically stored as a powder at -20°C. Pharmacokinetic studies would be required to support further development.

Detailed toxicology data for KS176 are limited in publicly available sources. As a BCRP inhibitor, the compound's toxicity profile may be related to effects on normal tissues that express BCRP. Standard preclinical safety evaluation would be required for further development. The compound's selectivity for BCRP over P-gp and MRP1 suggests a favorable safety profile.

ChemMedChem.2010 Sep 3;5(9):1498-505.

Structure in the first source
KS176 is a potent and selective inhibitor of the BCRP multidrug transporter with IC₅₀ values of 0.59 μM in Pheo A assays and 1.39 μM in Hoechst 33342 assays. It has no inhibitory activity against P-gp or MRP1. KS176 has a molecular formula of C₂₂H₁₉N₃O₅ and a molecular weight of 405.4 g/mol. The compound is used in cancer research to study BCRP-mediated multidrug resistance and to develop strategies for overcoming drug resistance.

C22H19N3O5

405.4

405.132

C, 65.18; H, 4.72; N, 10.37; O, 19.73

1253452-78-6

49779726

White to off-white solid powder

4.303

3

5

6

30

592

0

C1=CC=C(C(=C1)C(=O)NC2=CC=C(C=C2)CCO)NC(=O)C3=CC=C(C=C3)[N+](=O)[O-]

LTWQQWSXYYXVGA-UHFFFAOYSA-N

InChI=1S/C22H19N3O5/c26-14-13-15-5-9-17(10-6-15)23-22(28)19-3-1-2-4-20(19)24-21(27)16-7-11-18(12-8-16)25(29)30/h1-12,26H,13-14H2,(H,23,28)(H,24,27)

N-[4-(2-Hydroxyethyl)phenyl]-2-[(4-nitrobenzoyl)amino]benzamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)