Other targets of drug action

Drugs used in the clinic can have targets other than the major families of receptors, enzymes and ion channels. Pharmacologically important examples include but are not limited to transporters (both as drug targets and for their ability to modify drug action), structural components of the cell such as tubulin, and DNA (and RNA).

Monoamine reuptake transporters

Monoamine reuptake inhibitors (MRIs) reduce the reuptake of one or more of the three major monoamine neurotransmitters, serotonin (5-hydroxytryptamine), norepinephrine, and dopamine by inhibiting the transporters responsible for their reuptake from the synaptic cleft. These transporters are the serotonin transporter (SERT, SLC6A4), norepinephrine transporter (NET, SLC6A2), and dopamine transporter (DAT, SLC6A3) respectively. The majority of currently approved antidepressants, including almost all of the tricyclic antidepressants (TCAs), act as MRIs. Antidepressants are often sub-divided into groups according to their transporter selectivity e.g. selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Psychostimulants used to treat ADHD act as MRIs (e.g. methylphenidate (Ritalin), a NET/DAT MRI). Psychostimulants are often abused as recreational drugs and this has spawned the synthesis of so-called 'designer drugs' or 'new psychoactive substances' (NPS) such as mephedrone, which acts to both increase release of monamines and inhibit their reuptake (see PubChem CID 45266826 for Mechanism of action details).

König et al. (2013) provide a review of drug-drug and drug-food interactions which can affect uptake and efflux transporters involved in determining drug disposition and effects. Some of the important transporter families are discussed below.

ABC transporters and multi-drug resistance

A subset of ABC transporters use energy from ATP hydrolysis to export a large variety of drugs from the cytosol to the extracellular medium. In multidrug-resistant cells, the gene for the multidrug resistance protein 1 (MDR1, P-glycoprotein), ABCB1 is frequently amplified in cancer cells, where it facilitates an abnormally high level of drug molecule expulsion from the cell. This can reduce the drug concentration to an ineffective level. The anti-tubulin drugs colchicine and vinblastine are transported out of the cell by ABCB1. ABCG2 (a.k.a. BCRP, breast cancer resistance protein) confers resistance to most Topoisomerase I or II inhibitors, including topotecan, irinotecan, mitoxantrone and doxorubicin, anthracycline anticancer drugs and is inhibited by cyclosporin A. Multidrug resistance-associated protein 1 (MRP1, ABCC1) is a member of the MRP (multidrug resistance proteins) subfamily of ABC transporters, in this case confering resistance to methotrexate and glutathione and glucuronate conjugates from phase II xenobiotic detoxification. The CFTR, the transporter whose loss-of -function mutation causes cystic fibrosis is an ABCC subfamily member (ABCC7) as well as being considered a chloride channel, as are the sulfonylurea receptors, SUR1 and SUR2. The SURs are involved in insulin secretion, neuronal function, and muscle function, and mutation of these genes may cause neonatal diabetes mellitus.

SLC (solute carrier) transporters

The SLC family of transport proteins expend energy to move a range of different solutes across biological membranes. Family members include the OATP, OAT, OCT, and the MATE transporters, located predominantly in the intestine, blood brain barrier, kidneys and liver where they influence the absorption, distribution, metabolism and excretion of drugs. During the drug development process potential interactions with specific SLCs must be considered, due to the role these proteins play in clinical drug-drug interactions and the impact of genetic polymorphism of some of these transporters on therapy outcome and toxicity. The main SLCs of concern are OATP1B1 (SLCO1B1), OATP1B3 (SLCO1B3), OAT1 (SLC22A6), OAT3 (SLC22A8) and OCT2 (SLC22A2) and to a lesser extent OCT1 (SLC22A1), MATE1 (SLC47A1) and MATE2 (SLC47A2).

Drugs which are inhibitors or substrates for SLC transporter activity 

TransporterSubstrate/Inhibitor
OATP1B1rifamycin, cyclosporin A, methotrexate
OATP1B3rifampicin, cyclosporin A, methotrexate
OATP2B1rifamycin, ritonavir, atorvastatin
OAT1probenecid, diclofenac
OAT3probenecid, diclofenac
OCT1verapamil, quinidine
OCT2verapamil, quinidine, metformin
MATE1cimetidine, verapamil
MATE2cimetidine, verapamil

Other transporters

Glucose transporters facilitate the transport of hydrophilic glucose in to cells, to maintain a ready supply of glucose as an essential source of metabolic energy. Discovering that GLUT1 (SLC2A1) overexpression allows cancer cells to survive in hypoxic microenvironments, and that GLUT1 inhibitors can cause apoptotic death in cancer cells whilst sparing normal cells, has made GLUT1 a target of interest in cancer research, as are glycolytic inhibitors.

Sodium/glucose cotransporters (a.k.a. sodium-glucose linked transporters or SGLTs) contribute to renal glucose reabsorption. SGLT2 (SLC5A2) is a drug target for the treatment of diabetes, with the 'gliflozins' dapagliflozin, canagliflozin and empagliflozin approved for type II diabetes. These drugs act on SGLT2 in the renal proximal convoluted tubule to reduce glucose reabsorption and increase glucose excretion in the urine.


Cytoskeletal targeting compounds are small molecules that interact with actin or tubulin. They can either

  • stabilise cytoskeletal components
  • prevent polymerisation of monomers into filaments
  • enhance de-polymerisation of already formed filaments

Actin-targeting compounds have not been transferred to the clinic, but are useful experimental tools used to further understanding of how the actin machinery in cells works.

Microtubule targeting compounds have been much more successful clinically, with the anti-cancer 'taxanes' paclitaxel, cabazitaxel, docetaxel, being extremely useful in a number of cancer types. The taxanes are pan-tubulin inhibitors which interfere with microtubule structure, thereby disrupting cellular functions such as mitosis, to effect cell death. Other tubulin-targeting drugs are listed in the table below.

Cytoskeletal drugs, their actions and clinical uses.

Drugcytoskeletal targetMechanism of actionClinical use
colchicinemicrotubulesprevents tubulin polymerizationgout treatment
docetaxelmicrotubulesanti-mitotic; stabilizes microtubuleschemotherapy
eribulinmicrotubulesanti-mitotic; causes apoptosischemotherapy
paclitaxelmicrotubulesanti-mitotic; stabilizes microtubuleschemotherapy
vinblastinemicrotubulesprevents tubulin polymerizationchemotherapy

 


Alkylating agents were one of the earliest classes of drugs used to treat cancer. They disrupt DNA structure and formation to cause irreparable DNA damage in cancer cells which ultimately leads to cell death.

The five major categories of alkylating agents are:

Nitrogen mustards- e.g. mechlorethamine, ifosfamide, melphalan, chlorambucil, estramustine and cyclophosphamide

Nitrosoureas- e.g. streptozocin, carmustine, bendamustine and lomustine

Alkyl sulfonates- e.g. busulfan and treosulfan

Triazines- e.g. dacarbazine and temozolomide

Ethylenimines- e.g. thiotepa and altretamine

Some cancers can develop resistance to alkylating agents, by utilising the activity of the enzyme O-6-methylguanine-DNA methyltransferase (MGMT) to repair the alkylating agent-induced DNA damage. For example, MGMT is able to repair methyl group damage on guanine nucleotides in DNA caused by temozolomide, thus negating its antineoplastic effect.


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