Ko 143 is a potent and selective inhibitor of breast cancer resistance protein (BCRP; ABCG2) with an IC50 value of 23nM[1]. BCRP is an important transmembrane efflux transporter in the body and belongs to the ATP-binding cassette transporter superfamily. It is mainly responsible for the excretion of endogenous and exogenous substances into the extracellular space[2]. The selectivity of Ko 143 is more than 200 times that of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1)[3].
In vitro, Ko 143 (1.5µM) treatment of U251-V cells expressing ABCG2 for 4h inhibited ABCG2 and restored the intracellular accumulation of the photosensitizer dihydrochlorin e6 (Ce6)[4]. Ko 143 (1μM) treatment of MCF7 cells significantly increased the intracellular fluorescence of mitoxantrone[5]. Treatment of HeLa1A1 cells expressing UGT1A1 with Ko 143 (5, 20μM) significantly reduced the cellular excretion of DMC-O-glucuronide[6].
In vivo, oral treatment of Mdr1a/1b-/- mice with Ko 143 (10mg/kg) increased the oral availability of topotecan and increased its plasma concentration by 4-6 fold at 30 and 60min after administration[7].
References:
[1] Yu Q, Dehghani-Ghahnaviyeh S, Rasouli A, et al. Modulation of ABCG2 Transporter Activity by Ko143 Derivatives[J]. ACS Chemical Biology, 2024, 19(11): 2304-2313.
[2] Choudhuri S, Klaassen C D. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters[J]. International journal of toxicology, 2006, 25(4): 231-259.
[3] Lustig S D, Kodali S K, Longo S L, et al. Ko143 reverses MDR in glioblastoma via deactivating P-glycoprotein, sensitizing a resistant phenotype to TMZ treatment[J]. Anticancer Research, 2022, 42(2): 723-730.
[4] Gaber S A A, Müller P, Zimmermann W, et al. ABCG2-mediated suppression of chlorin e6 accumulation and photodynamic therapy efficiency in glioblastoma cell lines can be reversed by KO143[J]. Journal of Photochemistry and Photobiology B: Biology, 2018, 178: 182-191.
[5] Wang J S, Zhu H J, Markowitz J S, et al. Antipsychotic drugs inhibit the function of breast cancer resistance protein[J]. Basic & clinical pharmacology & toxicology, 2008, 103(4): 336-341.
[6] Zhang B, Yang J, Qin Z, et al. Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1[J]. Plos one, 2019, 14(5): e0217695.
[7] Allen J D, Van Loevezijn A, Lakhai J M, et al. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C[J]. Molecular cancer therapeutics, 2002, 1(6): 417-425.
Ko 143是一种有效的选择性乳腺癌耐药蛋白（BCRP; ABCG2）抑制剂，IC50值为23nM[1]。BCRP是体内重要的跨膜外排转运体，属于ATP结合盒转运体超家族，主要负责将内、外源性物质排至细胞外[2]。Ko 143的选择性是P-糖蛋白（P-gp）和多药耐药蛋白-1（MRP-1 ）的200倍以上[3]。
在体外，Ko 143（1.5µM）处理表达 ABCG2的U251-V细胞4h，抑制了ABCG2，恢复了光敏剂二氢卟酚e6（Ce6）在细胞内的积累[4]。Ko 143（1μM）处理MCF7细胞，显著增加了米托蒽醌（mitoxantrone）的细胞内荧光[5]。Ko 143（5、20μM）处理表达UGT1A1的HeLa1A1细胞，显著减少了DMC-O-葡萄糖醛酸苷的细胞排泄[6]。
在体内，Ko 143（10mg/kg）通过口服治疗Mdr1a/1b-/-小鼠，给药后30min和 60min，增加了拓扑替康（topotecan）的口服可用性，使其在血浆的浓度升高了4-6倍[7]。