Review articleUpdated chemical scaffolds of ABCG2 inhibitors and their structure-inhibition relationships for future development
Graphical abstract
Introduction
In cancer chemotherapy, multidrug resistance (MDR) is typically the main barrier to success and ineffectiveness of treatment [[1], [2], [3], [4], [5]]. Numerous studies have revealed that the primary reason behind the MDR is overexpression of the ABC (ATP binding cassette) transporters [[6], [7], [8], [9], [10], [11], [12]]. ABC transporter proteins are found in all prokaryotic and eukaryotic cells. In humans, these are mainly found on the plasma membrane. Based on the phylogenetic subfamily, there are various types of ABC transporters’ subfamily (designated by the letters A to G). ATP binding cassette subfamily B member 1 (ABCB1, also known as p-glycoprotein), ABCC1 (multidrug resistance-associated protein or MRP1) and ABCG2 (breast cancer resistance protein or BCRP) are important members of the group involved in MDR [[13], [14], [15], [16], [17]]. P-glycoprotein was the first MDR protein identified that was isolated from human KB carcinoma cells in 1986 and selected for resistance to colchicine, vinblastine, and adriamycin (doxorubicin). In 1992, a second MDR causing transporter MRP1 was discovered that belongs to the ABC subfamily C and was found to cause resistance to xenobiotics. ABCG2 contains one nucleotide-binding domain (NBD) and one transmembrane domain (TMD) fused to a single polypeptide chain. The functional form of this transporter is a homodimer [5,7,15,18]. This transporter is localized in various parts of the body including the blood-brain barrier (BBB), blood-testis barrier (BTB), blood placental barriers (BPB), blood-retinal barriers (BRB), the luminal surface of liver canaliculi and renal proximal convoluted tubules. Since the ABCG2 transporter is localized on the surfaces of excretory organs, it modulates the absorption, distribution, metabolism, and elimination (ADME) of certain drugs. The same transporter, known as ABCP (placenta-specific ABC transporter) and MXR1 (mitoxantrone-resistance gene), was discovered in two separate studies, one in the human placenta and the other in drug-resistant cancer cells chosen in mitoxantrone. The substrates of the ABCG2 transporter are primarily hydrophobic molecules including methotrexate, mitoxantrone, flavopiridol, topotecan, and SN-38 [5].
The interest to develop an effective ABCG2 inhibitor was tremendously increased particularly after the failure of the p-glycoprotein inhibitor in the clinic [7]. The high expression of ABCG2 protein in different types of solid tumors especially the cancers of the digestive tract, endometrium, lungs and melanoma makes ABCG2 an excellent drug target for possible cancer resistance. Only a few of the diverse ABCG2 inhibitors that were developed in the search for efficient cancer therapies were tested in clinical trials. The negative outcomes of clinical trials with various ABCG2 inhibitors emphasize the necessity of revisiting this target clinically in order to address the growing issue of cancer drug resistance, as well as the need to simultaneously develop novel, potent inhibitors for upcoming clinical trials [7,8]. The primary focus of this work has been on the many forms of ABCG2 inhibitors and their structure-inhibition interactions (SIRs). The detailed knowledge of the inhibitors will be useful not only in developing inhibitors with improved activity and selectivity for future clinical trials, but also in avoiding potentially lethal drug interactions with ABCG2.
Section snippets
A short trip to ABC transporter
ABC transporters are the largest group of transmembrane (TM) proteins, grouped into seven subfamilies (ABCA to ABCG) based on sequence homology which is found in the human genome [[19], [20], [21], [22], [23], [24]]. ABC transporters help to transfer diverse substances through the membrane against concentration gradients but three of them (ABCB1, ABCC1 and ABCG2) have been shown to mediate the chemoresistance of cancer cells by extruding anticancer drugs from the tumor cells. There are some
Functional structure of human ABCG2 protein
ABCG2 is a glycoprotein containing 655 amino acids and has a molecular weight of approximately 70 kDa. The gene of ABCG2 is present in chromosomes 4q22.1 [21,22]. Human has a distinctive modular architecture of ABCG2 transporters as revealed by the different structures of the protein (Table 2) [14,[21], [22], [23], [24]].
The structures were reported with different substrates like Mitoxantrone, SN38, Estrone 3-sulfate, etc. as well as potent inhibitor like MZ29 and weak inhibitor like MB136.
Mechanism of inhibition of ABCG2
TMD is the main binding site of the ABCG2 protein where most of the ligands or inhibitors interact. ABCG2 is reported to be present in apo form at the normal stage, but when ligand binding occurs via hydrophobic interactions in the substrate-binding region at the dimer interface, its conformation changes to an inward-facing conformation [21]. The transporter is then reset to the apo-closed conformation by ATP binding in the ATP binding site, which promotes substrate efflux to the extracellular
Interaction of inhibitors and ABCG2 protein
Orlando and Liao demonstrated the fascinating behaviour of ABCG2 protein upon ligand binding [21]. A specific ligand may induce a conformational change of ABCG2. Imatinib and Ko143 favour stabilization of the inward-facing conformation and subsequently inhibit ATPase activity by promoting the 5D3 antibody binding. In contrast, transport substrates like SN38 and MXN cause the protein to shift toward the inward-facing conformation in which the small molecules are trapped at the dimer interface.
Inhibitors of ABCG2
The knowledge of the design of inhibitors targeting ABCG2 is essential to understand its structure-inhibition relationship. Different types of p-glycoprotein inhibitors (for instance GF120918/compound 1 in Fig. 4) were reported before the discovery of ABCG2 inhibitors [26], but no specific one could inhibit both ABCB1 and ABCG2. Fumitremorgin C (FTC, compound 2 in Fig. 4) was isolated from Aspergillus fumigatus that showed the capability to inhibit the ABCG2 [27].
Researchers discovered the
Expert opinion
Few ABC transporter families play a crucial role in MDR, and ABCG2 is one of them. Researchers designed and investigated different scaffolds for inhibition of transporter proteins but only a few of them showed inhibitory effects in the picomolar range and some of them did not show any inhibitory effect at all. Now in recent times there has been no marketed product as ABCG2 inhibitor. Thus, the design of novel ABCG2 inhibitors is critical yet unavoidable in order to stop MDR in the current
Conclusion
MDR is the main drawback of cancer chemotherapy and this is due to the overexpression of the ABC transporter proteins. The last few years witnessed the emergence of different series of small molecules as potent and highly selective ABCG2 inhibitors. Although, researchers have discovered different types of scaffolds for inhibiting the ABCG2, no effective drug has been found. In this review, we discussed the mechanisms of action, binding interaction and structure-inhibition relationships (SIRs)
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
Md. Moinul is grateful to All India Council of Technical Education (AICTE), New Delhi for awarding postgraduate GPAT fellowship. Sk. Abdul Amin sincerely acknowledges Council of Scientific & Industrial Research (CSIR), New Delhi, India for awarding the Senior Research Fellowship [FILE NO.: 09/096(0967)/2019-EMR-I, Dated: 01-04-2019]. Ms. Samima Khatun of Jadavpur University, Kolkata, India is gratefully acknowledged for her critical reading and corrections of the manuscript. Sk. Abdul Amin
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Authors have equal contribution.