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 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.
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.
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).
| Transporter | Substrate/Inhibitor |
|---|---|
| OATP1B1 | rifamycin, cyclosporin A, methotrexate |
| OATP1B3 | rifampicin, cyclosporin A, methotrexate |
| OATP2B1 | rifamycin, ritonavir, atorvastatin |
| OAT1 | probenecid, diclofenac |
| OAT3 | probenecid, diclofenac |
| OCT1 | verapamil, quinidine |
| OCT2 | verapamil, quinidine, metformin |
| MATE1 | cimetidine, verapamil |
| MATE2 | cimetidine, verapamil |
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
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.
| Drug | cytoskeletal target | Mechanism of action | Clinical use |
|---|---|---|---|
| colchicine | microtubules | prevents tubulin polymerization | gout treatment |
| docetaxel | microtubules | anti-mitotic; stabilizes microtubules | chemotherapy |
| eribulin | microtubules | anti-mitotic; causes apoptosis | chemotherapy |
| paclitaxel | microtubules | anti-mitotic; stabilizes microtubules | chemotherapy |
| vinblastine | microtubules | prevents tubulin polymerization | chemotherapy |
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.