Review article
Updated chemical scaffolds of ABCG2 inhibitors and their structure-inhibition relationships for future development

https://doi.org/10.1016/j.ejmech.2022.114628Get rights and content

Highlights

  • ABCG2 is a transporter involved in the efflux of some chemotherapeutic agents.

  • An exquisite picture of the structure-inhibitory relationships of ABCG2inhibitors is provided.

  • A list of essential structural features to be considered in the design of successful ABCG2 inhibitor was discussed.

Abstract

ATP-binding cassette (ABC) transporters are pivotal for cell detoxification and survival. Overexpression of ABC transporter in tumor cells lead to chemoresistance through the efflux of chemotherapeutic agents. P-glycoprotein (Pgp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) are the major ABC transporters involved in multidrug resistance (MDR) of cancer cells against anticancer drugs. ABCG2 is one of the major transporters involved in the efflux of different cytotoxic agents. Hence, inhibition of ABCG2-mediated transport is considered a prime target to resist MDR of cancer cells. Here, brief structural biology and functions of ABCG2 were discussed with the aim to identify key pharmacophoric elements to design potent and selective as well as non-toxic ABCG2 inhibitors. Structure-inhibition relationships (SIRs) of the earlier reported compounds were also explored. Taken together, this study offers insight for further development of ABCG2 inhibitors.

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

References (90)

  • E. Nicolle et al.

    Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach

    Eur. J. Pharmaceut. Sci.

    (2009)
  • A.D.R.A. Pires et al.

    New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2

    Eur. J. Med. Chem.

    (2016)
  • E. Roussel et al.

    Optimization of the chromone scaffold through QSAR and docking studies: identification of potent inhibitors of ABCG2

    Eur. J. Med. Chem.

    (2019)
  • E. Roussel et al.

    Chromones bearing amino acid residues: easily accessible and potent inhibitors of the breast cancer resistance protein ABCG2

    Eur. J. Med. Chem.

    (2020)
  • C. Cai et al.

    Biological evaluation of non-basic chalcone CYB-2 as a dual ABCG2/ABCB1 inhibitor

    Biochem. Pharmacol.

    (2020)
  • K. Silbermann et al.

    Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2

    Eur. J. Med. Chem.

    (2019)
  • F. Antoni et al.

    Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)

    Eur. J. Med. Chem.

    (2020)
  • M.K. Krapf et al.

    Synthesis and biological investigation of 2,4-substituted quinazolines as highly potent inhibitors of breast cancer resistance protein (ABCG2)

    Eur. J. Med. Chem.

    (2017)
  • M.K. Krapf et al.

    Synthesis and biological evaluation of quinazoline derivatives - a SAR study of novel inhibitors of ABCG2

    Eur. J. Med. Chem.

    (2019)
  • J. Kwak et al.

    Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel

    Eur. J. Pharmacol.

    (2010)
  • Z.X. He et al.

    Pyrimidine: a promising scaffold for optimization to develop the inhibitors of ABC transporters

    Eur. J. Med. Chem.

    (2020)
  • C.Y. Cai et al.

    Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance

    Eur. J. Med. Chem.

    (2019)
  • C. Karthikeyan et al.

    Pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolines: novel compounds that reverse ABCG2-mediated resistance in cancer cells

    Cancer Lett.

    (2016)
  • C. Zaehle et al.

    Terrein biosynthesis in Aspergillus terreus and its impact on phytotoxicity

    Chem. Biol.

    (2014)
  • K.W. Tan et al.

    Dietary polyacetylenes of the falcarinol type are inhibitors of breast cancer resistance protein (BCRP/ABCG2)

    Eur. J. Pharmacol.

    (2014)
  • A.F. Wilks

    Structure and function of the protein tyrosine kinases

    Prog. Growth Factor Res.

    (1990)
  • A.K. Tiwari et al.

    Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters

    Biochem. Pharmacol.

    (2009)
  • G.N. Zhang et al.

    Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib

    Pharmacol. Res.

    (2017)
  • Y.F. Fan et al.

    Dacomitinib antagonizes multidrug resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters

    Cancer Lett.

    (2018)
  • C. Pucci1a et al.

    Innovative approaches for cancer treatment: current perspectives and new challenges

    Ecancermedicalscience

    (2019)
  • N.M.I. Taylor et al.

    Structure of the human multidrug transporter ABCG2

    Nature

    (2017)
  • S.M. Jackson et al.

    Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

    Nat. Struct. Mol. Biol.

    (2018)
  • S. Kokubo et al.

    A phenylfurocoumarin derivative reverses abcg2-mediated multidrug resistance in vitro and in vivo

    Int. J. Mol. Sci.

    (2021)
  • R. Eckenstaler et al.

    3D structure of the transporter ABCG2- what's new?

    Br. J. Pharmacol.

    (2020)
  • K. Ghosh et al.

    Identification of structural fingerprints for ABCG2 inhibition by using Monte Carlo optimization, Bayesian classification, and structural and physicochemical interpretation (SPCI) analysis

    SAR QSAR Environ. Res.

    (2020)
  • D.J. Brackman et al.

    Reverse translational research of ABCG2 (BCRP) in human disease and drug response

    Clin. Pharmacol. Ther.

    (2018)
  • R.W. Robey et al.

    Revisiting the role of ABC transporters in multidrug-resistant cancer

    Nat. Rev. Cancer

    (2018)
  • B.L. Abbott

    ABCG2 (BCRP): a cytoprotectant in normal and malignant stem cells

    Clin. Adv. Hematol. Oncol.

    (2006)
  • K. Nosola et al.

    Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1

    Proc. Natl. Acad. Sci. U.S.A.

    (2020)
  • S.P. Cole et al.

    Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

    Science

    (1992)
  • Q. Yu et al.

    Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism

    Nat. Commun.

    (2021)
  • Y.L. Sun et al.

    Role of ABC transporters in cancer chemotherapy, Chin

    J. Cancer

    (2012)
  • Z. Ni et al.

    Structure and function of the human breast cancer resistance protein (BCRP/ABCG2)

    Curr. Drug Metabol.

    (2010)
  • B.J. Orlando et al.

    ABCG2 transports anticancer drugs via a closed-to-open switch

    Nat. Commun.

    (2020)
  • I. Manolaridis et al.

    Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states

    Nature

    (2018)
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