Great things start small: an insight into fragment based drug discovery

Have you ever noticed that great things almost always start small? Take for example Richard Branson, he started the Virgin brand with a student magazine!.

We want ‘big’ things, we have ‘big’ aspirations, we want to jump ‘big’ too soon without thinking that maybe starting from small is the best way to go.

Nowadays, drug development is adopting this thought as well: start small. And this can be achieved by screening for small chemical fragments that bind only weakly to a biological target and only then growing them or combining them to produce a compound with higher affinity. This method is known as fragment-based drug discovery (FBDD) and the main topic of this post.

Think small, think FBDD

Developing a new drug is a complex process. Once the target has been chosen, the process of lead discovery begins. A lead is a compound from a series of related compounds that has some of a desired biological activity. A variety of methods to identify hit molecules exist, but the most commonly used is high-throughput screening (HTS), in which libraries with up to millions of compounds with molecular weights of around 500 daltons are screened and nM binding affinities to target are sought. But could we think ‘small’? Smaller molecules, smaller affinities? Definitely YES.

In contrast with HTS, in FBDD typically about 1,000 fragments are screened using biophysical techniques. The fragments are between 150-250 daltons and mM affinities can be considered useful. After biophysical analysis, candidate fragments are grown to form new interactions using structure-based drug design. Although initial fragment hits have low potency due to their small size, they form high-quality interactions and can be readily optimized into potent lead molecules.

Does size matters then? YES, because the size, complexity and physical properties of small molecules can be more easily controlled than when starting from higher affinity HTS hit.

How can fragment binding be screened?

Biophysical methods to screen fragment binding to its target include NMR spectroscopy, X-ray diffraction, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR) and mass spectrometry. Which one to use? Each method has advantages and disadvantages in terms of sample consumption, degree of automation and assay complexity, but the general rule is that whatever method you choose, it has to be FAST, EFICIENT, PRECISE and to REDUCE THE NUMBER OF FALSE POSITIVES AND FALSE NEGATIVES. Remember that the number of fragments that are frequently analyzed can go from hundreds to thousands, so it is very important to choose well.

A new effective method for fragment screening

An emerging technique has appeared very recently for fragment screening¹. Microscale thermophoresis (MST) has been broadly applied to investigate biomolecular interaction of a variety of drug targets, thus it seemed perfect for trying it in FBDD… and it is.

In a recent fragment screening made by Sanofi, MST was used in an automated manner to screen a library of fragments targeted against the kinase MEK1 from the MAPK signalling cascade, thus with looks into developing anticancer therapies. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods.

But what I found great about this technology and what marks a difference is related to an important aspect of fragment screening campaigns: The EXCLUSION OF FALSE POSITIVES AND FALSE NEGATIVES. Binding of fragments and small molecules can either stabilize or destabilize target proteins. Destabilization or denaturation of proteins is often accompanied by protein aggregation and MST provides a direct feedback on ligand-induced aggregation and other secondary effects. Thus the information provided by MST prevents false-positive hits from entering later stages of hit expansion, as well as rescuing fragments classified as false negatives.

All in all, this speed technology, used in conjunction with other biophysical techniques has the potential to significantly improve FBDD workflows.

In the early days of FBDD there was some scepticism that it would ever work, for example, “How can such low-affinity compounds be identified?” or “Drug discovery is hard enough starting with a high affinity hit so why go to smaller and lower affinity compounds?”. Today, the consensus has changed. At least nine FBLD projects have led to compounds in phase II or III studies, including one approved drug. The fragment approach has been adopted throughout academia and large pharma and biotech companies, and there are a number of commercially available fragment libraries.

So think about it……… maybe it’s time for you to start small.

“Start small, think big. Don’t worry about too many things at once. Take a handful of simple things to begin with, and then progress to more complex ones. Think about not just tomorrow, but the future. Put a ding in the universe”. Steve Jobs.

1. Linke, P., Amaning, K., Maschberger, M., Vallee, F., Steier, V., Baaske, P., Duhr, S., Breitsprecher, D., Rak, A. An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery. 2015. Journal of Biomolecular Screening. doi:10.1177/1087057115618347

Biosimilars are the next money makers of pharma industry

It has happened to everyone: got sick, went to the doctor, got diagnosed and received that desired white piece of paper named “drug prescription”. We run to the drugstore and just ask straight ahead for what has been prescribed. Until recently not many options regarding price of the drug or effect were available, but now some alternatives are there for us.

GENERIC DRUGS are one alternative. They are copies of brand-name drugs, and by ‘copies’ I mean in dosage, safety, strength, route of administration, quality, performance, characteristics and intended use. They have the exact same ‘active component’ of the brand name drug, which is the part that has the therapeutic function, while the ‘inactive components” which in general do not have any pharmacological effect can be different, and they can include dyes, preservatives, flavouring agents, etc.

Generic drugs are important options that allow greater access to health care… why?? BECAUSE THEY ARE WAY CHEAPER THAN BRAND NAME DRUGS. The latter are developed under a patent, which protect a drug company’s investment in developing the drug. This gives the company EXCLUSIVE RIGHTS to sell the drug while the patent is in effect for up to 17 years. After the patent expires, other drug companies can produce the drug. But generic drugs are able to be sold for lower prices because they are not required to repeat the costly clinical trials of new drugs and generally do not pay for costly advertising and marketing. In addition, multiple generic companies are often approved to market a single product; this creates competition in the market place often resulting in lower prices. Good for us consumers. (Story not told, is that 70 to 80% of all generic drugs are produced by the same companies who make brand name drugs… obviously).

BIOSIMILARS, the new kid on the block, are another alternative. They are biological products (not chemicals such as brand name and generic drugs) highly similar to brand name drugs with no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. They also differ from ‘generics’ in that THEY ARE NOT EXACT COPIES of brand name drugs.

Producing generic small-molecule drugs is relatively simple–it’s like following a recipe with standard ingredients. Biosimilars are much more challenging because living cells (where they are produced) are highly sensitive to their environments, and manufacturers have to create their own, unique process to make these cells to produce an identical outcome to an existing treatment.

Biosimilars have made drug approvals challenging. Generics are approved based on matching chemical structure, but that doesn’t work for biosimilars. Each new biosimilar has to run clinical trials to prove the outcome matches that of the biologic it is imitating, even though it looks structurally different, according to recently announced guidelines from the Food and Drug Administration.

Let’s talk about money

When talking about Pharma business there is a lot of money involved and the opportunities for biosimilars are huge for both manufacturers and consumers. Many leading biologic medicines worth more than $81 billion global annual sales will lose their patent protections by 2020… only 4 more years, that means the war between pharma companies has begun.

Much like generics, biosimilars can help cut drug costs, though the savings are smaller because of their complexity as well as regulatory challenges of getting FDA approvals. Biosimilars cost about $75 million to $250 million to reach the approval stage, versus around $2 million to $3 million for a generic small-molecule medicine.

So far, an inflexion point in the pharmaceutical industry has been seen with the approval of two biosimilars: the Hospira’s biosimilar version of infliximab (a monoclonal antibody used to treat autoimmune diseases) in Europe and the subsequent approval in the U.S. of its first biosimilar in history, Novartis’ Zarxio (which targets Amgen’s Neupogen).

In September 2015, Pfizer  shelled out big bucks–$17 billion to be exact–to buy the much smaller drugmaker Hospira. A big reason for the rather expensive acquisition is to gain access to the company’s biosimilar portfolio, an insight on how important these new drugs are becoming for pharma industry.

What can be expected then? Well, that some of the big firms — including Abbvie, Roche and Pfizer — will be highly impacted by how this biosimilar market shapes up in near future. There are around 11 biosimilars under development to compete with Abbvie’s Humira (infliximab competitor) alone, which loses its patent exclusivity in the U.S. in 2016.

Biosimilars are extending to the rest of the world as well. Last month, Brazil registered the first latin-american biosimilar (filgrastim), one of the 20 existing biosimilars to date.

What’s great about these drugs is that many people will definitely benefit as biosimilars take off. Significant savings for medical programs will be seen, since the worldwide trends is that governments are pushing theirselves for granting marketing authorizations for biosimilars…. I hope less money spend in health means more money spent for good purposes for us all tax-payers.