Blog – Page 48 – Drug Discovery Opinion

New Drugs Could Make Tumour Cells More Sensitive to Radiotherapy

In the rare inherited human disease, ataxia-telangiectasia (A-T), a mutation is present in a gene encoding a protein that normally activates cellular responses to DNA damage. The mutation in the ATM gene leads to decreased ability to repair damaged DNA, and an increased sensitivity to ionising radiation and other DNA damaging agents. This highlights the ATM pathway as a potential target to increase the sensitivity of tumour cells to radiotherapy or chemotherapy. The ATM protein demonstrates kinase activity and a selective, small molecule inhibitor of this kinase, CP466722, has now been shown to enhance the sensitivity of tumour cells grown in vitro to ionising radiation.

Inhibition of ATM kinase activity is rapid, and is completely and rapidly reversed on wash-out; further experiments suggested that inhibition of ATM for a short period of time may be sufficient to sensitise tumour cell to radiotherapy. Because CP466722 is effective in murine cells as well as human cells, it may be possible to use mouse models to further explore the potential of using ATM inhibitors to increase the effectiveness of radiotherapy.

New Drug May Prevent Multiple Sclerosis

Multiple sclerosis (MS) is a disorder of the central nervous system with initial inflammation of the protective myelin sheath encasing nerve fibres. Symptoms vary widely and often occur initially as discrete episodes interspersed with relatively symptom-free periods (relapsing MS).

A drug currently being tested for its effectiveness in treating relapsing forms of MS is now to be tested to see whether it can prevent the disease from developing. The drug, cladribine, will be given orally to patients who have a first clinical event suggestive of MS. Patients will be treated for two years, or up to the time when they experience a second attack leading to a definite clinical diagnosis of MS. Treatment will be given in two or four cycles in the first year, with a single daily dose of cladribine tablets being given on four to five consecutive days in each cycle. This means that patients in the study will take cladribine for only 8 – 20 days in the first year. In the second year, two treatment cycles will be given to all patients.

Cladribine is also used as an intravenous infusion to treat hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphomas.

Botox Shown to Work for Chronic Migraines

Migraine is very prevalent worldwide. Attacks are more common in women and can occur at any age, but often diminish after the age of 50. Migraine pain is usually described as a severe throbbing or pulsating headache, often with nausea and sensitivity to light, which can last for many hours or even days.

The benefits of Botulinum Toxin (Botox®) in migraine were discovered accidentally when injections to reduce lines and wrinkles were reported to reduce the frequency and severity of headaches. Top-line analyses of data from two Phase III clinic trials confirm that Botox® is effective for the prophylaxis of chronic migraine. Patients were given Boxtox® or placebo injections every 12 weeks, and the primary analysis was carried out after two treatment cycles. The efficacy measures were the change in number of headache episodes and headache days compared with the 28 days preceding treatment. One study showed no significant reduction in the number of headache episodes between patients receiving Botox® and placebo, but a significant reduction in the number of headache days in the treatment group. The second study showed a benefit in terms of both number of headache episodes and headache days for the Botox® treated group. In both studies, patients receiving Botox® treatment reported significantly improved quality of life compared with patients receiving placebo.

New DPP-4 Inhibitor Demonstrates Glucose Control in Type 2 Diabetes

Type-2 diabetes is a metabolic disorder that is increasing rapidly in the developed world. The disease is caused by reduced production of insulin by the pancreas and /or reduced responsiveness to insulin by cells in the body, particularly fat, muscle and liver cells. Reduced insulin activity causes higher blood glucose levels as well as other complex metabolic changes, leading eventually to organ damage with increased morbidity and mortality.

A number of medicines are used to treat type-2 diabetes; these include metformin, sulphonyl ureas, and thiazolidinediones. More recently, inhibitors of dipeptidyl peptidase-4 (DPP-4) have emerged as an alternative method of treatment. DPP-4 inhibitors act by increasing levels of the gastrointestinal hormones, incretins, which increase the amount of insulin released by the pancreas, inhibit glucagon release and also slow gastric emptying.

New data has been presented showing that Januvia™ (sitagliptin), in combination with metformin, provided significant glucose lowering over two years. In separate studies, addition of Januvia™ to regimens based on thiazolidinediones also led to improved blood sugar control. Januvia™ was the first DPP-4 inhibitor to be approved for the treatment of diabetes in the US and Europe although several other inhibitors are in varying stages of development.

Small Molecules Lend a Hand in Protein Folding

Celastrol Protein folding is the process whereby newly synthesised linear polypeptide chains fold into the well-defined 3-dimensional shape of the functional protein. In many cases, molecular chaperones assist in correct protein folding by preventing the newly synthesised protein from aggregating into non-functional structures. A variety of diseases result from misfolded proteins; loss-of-function diseases are often caused by a point mutation in the sequence of the protein which disturbs the normal balance between protein folding and clearance. There has been recent interest in the development of ‘pharmacological chaperones’ which are small molecules that stabilise the correct protein fold.

God Vine A recent study describes two small molecules, celastrol and MG-132, that are able to enhance mutant protein folding and function in cell culture experiments. These compounds acted synergistically with known pharmacological chaperones and increased the activity of mutant proteins to 50% of wild-type activity. This study provides encouragement for the concept of developing regulators of proteostatis for the treatment of a range of loss-of-function diseases.

New Study Casts Light on Anti-Cancer Mechanism

A new study describes a high affinity interaction between siramesine and phosphatidic acid, a component of cell membranes that also acts as a signalling molecule. Siramesine is a sigma receptor agonist, selective for the σ2 subtype, which was originally under development for the treatment of anxiety but failed to show efficacy in clinical trials.

Siramesine was subsequently shown to kill cancer cells by destabilising their lysosomes. Vincristine, a microtubule destabilising antimitotic drug, which is used in various chemotherapy regimens, greatly sensitised cancer cells to the cytotoxic effects of siramesine.

The new study suggests that it may be possible to design small molecules to specifically scavenge phospholipids involved in the signalling cascades controlling cell survival.

Prostate Cancer and NSAID Use

Prostate cancer is the most common cancer in men, with the majority of cases occurring in the over-65s. Rising levels of prostate specific antigen (PSA) are associated with both localized and metastatic prostate cancer and a blood test for PSA is used for the early detection of the disease.

A recent study suggests that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen may reduce measured serum PSA levels, although it was unclear whether this indicated a protective effect against prostate cancer or whether use of NSAIDs obscured the test results. Paracetamol, which has very little anti-inflammatory activity, did not show a statistically significant effect on serum PSA levels.

Earlier studies have suggested that aspirin may reduce the risk of metastatic prostate cancer but not the total risk of prostate cancer and that combined long-term use of statins and NSAIDs might be associated with a reduced risk of prostate cancer.

Since prostate cancer cells show unusually high levels of the enzyme COX-2, which is inhibited by NSAIDs, there is considerable interest in the potential for COX-2 inhibitors in the treatment of prostate cancer and several clinical studies have been initiated.

New Antipsychotic Mechanism Discovered

PET scan It has been estimated that as many as 50 million people worldwide suffer from schizophrenia and many of these will be treated with antipsychotic medicines. The so-called typical antipsychotics have been available since the mid-1950s and a number of newer agents, the atypical antipsychotics, have been introduced since 1990. Increased dopaminergic activity is thought to be a contributory factor in schizophrenia and all of the antipsychotic medicines interact with the dopamine D2 receptor although they have different affinities and modulate the receptor in different ways.

A new study has shown that, regardless of their effect on G-protein coupled signalling via the D2 receptor, antipsychotic drugs potently antagonize the dopamine-mediated interaction of the D2 receptor with β-arrestin-2.

Arrestins are proteins that were initially found to regulate signal transduction by silencing GPCRs, although they have recently been shown to directly activate signalling pathways. The new results suggest that selective targeting of the interaction of D2 with β-arrestin-2 may provide a new opportunity for the development of antipsychotic medicines. More generally, targeting β-arrestin signalling pathways may open opportunities in other therapeutic areas.

New Target for Hepatitis C Treatment

Over 150 million people are estimated to be infected with the Hepatitis C virus. During the early stages of infection, the majority of people are free of symptoms but a significant number will later develop cirrhosis and possibly liver cancer.

Treatment is currently a combination of pegylated interferon-α and ribavirin, although several alternative therapies are being developed. Some of the more promising amongst these directly target essential viral enzymes such as the viral protease and polymerase.

The non-structural protein NS4B is an integral membrane protein that also plays a critical role in viral replication.

A new report shows that NS4B binds to viral RNA and describes the use of high-throughput microfluidic screening to identify compounds that inhibit this binding. 18 compounds that substantially reduced NS4B binding to its target RNA were discovered, and one of these compounds, clemizole, was found to inhibit replication of Hepatitis C virus in cell culture whilst showing little cellular toxicity.

Clemizole is an H1 histamine receptor antagonist and, because it has already been tested in people, it could be rapidly evaluated as a treatment for Hepatitis C infection.

Thinking Increases Food Intake

burger A study carried out in a small group of female students has shown that mental exercise increases food intake. In a ‘within-subjects’ study, each student spent 45 minutes resting, reading a document and writing a summary, or performing a battery of computerised tests. At the end of each 45 minute period, the students were invited to eat as much as they wanted from a buffet.

When the students had been involved in mental activity, they consumed 200 – 250 kilocalories more than when they had been resting. No specific dietary preferences or differences in appetite sensation markers were seen after mental exercise compared with resting. Mean cortisol levels were significantly higher and there was a significant increase in variations in plasma glucose and insulin levels after mental activity. Since the period of mental activity used almost no extra calories compared with resting, this study suggests a new risk factor for positive energy balance with the potential to lead to obesity.