Success in drug discovery is not necessarily fast or inevitable

The biotech industry rightly prizes speed: every day people die of diseases we are trying to prevent or cure. And developments can indeed happen quickly. Just eight years elapsed from the demonstration that a mutant form of KRAS was druggable to the approval of sotorasib, with less than three of those years spent in the clinic. Even more dramatically, it took less than a year from the first reports of SARS-CoV-2 to develop effective vaccines. But as two recent pieces in Nature Rev. Drug Disc. demonstrate, such speed is not necessarily the norm.

 

The first, by Asher Mullard, is entitled “FDA approves 100^th monoclonal antibody product.” This is a nice review of a remarkably successful therapeutic approach. But this triumph was not a foregone conclusion. Mullard traces the field’s origin to the mid-1970s, and while the first drug was approved in 1986, it took another eight years for the second. The article includes a timeline showing approvals by year, and it is interesting to compare this with FBDD-derived drug approvals since the 1996 publication of the seminal SAR by NMR paper. In the chart below, the first year on the x-axis is for antibody drugs; the second is for FBDD-derived drugs.

 

 

A quarter century after work began, new antibody approvals were still uncommon; Mullard notes that “antibody approvals have only been an annual event since 2006.”

 

Antibody-drug conjugates (ADCs) are an interesting subset that – as their name suggests – comprise an antibody linked to a small molecule, usually a toxin intended to kill cancer cells. Ten of these have been approved in the US, but while the first (gemtuzumab ozogamicin) was approved in 2000 most of the rest are recent, with six of them coming since the beginning of 2019.

 

By these standards the fact that only five fragment-derived drugs have been approved thus far isn’t surprising. Indeed, antibodies have some advantages: “whereas medicinal chemists can toil for years to find small molecules with activity against a given target, antibody discovery can take a matter of months.” Moreover, as the article continues, success in the clinic is roughly double that of small molecules.

 

The second article is by Christopher Austin, until recently Director of the National Center for Advancing Translational Sciences at the US National Institutes of Health. Titled “Translational Misconceptions,” it briefly enumerates and debunks false beliefs about translating new discoveries into drugs, which include:

 

- Translation does not exist 

 

- Translation is a “thermodynamically favored” process 

 

- Translation is straightforward and does not qualify as science 

 

- Translation is a unidirectional process 

 

- Once an investigational therapy gets into humans for the first time, regulatory approval

  and marketing are all but assured 

 

- Regulatory approval is the end of the translational process

 

Those of us in industry would probably dismiss these statements as naïve, but such perceptions are widespread. Indeed, Austin himself acknowledges that he “once believed unquestioningly in all of them.”

 

Each of these misconceptions invites discussion. To take just the last, the first approved ADC was pulled from the US market in 2010 when confirmatory trials showed that patients on the drug actually did worse than those on placebo. It was reapproved in 2017 after a better dosing schedule was established. In other words, it took 17 years after initial approval to figure out how to effectively use gemtuzumab ozogamicin, and 26 years from the beginning of the project.

 

Returning to the two successes mentioned at the top of this post reveals that their apparent rapidity does not tell the full story. The Tethering technology that eventually led to sotorasib was initially published more than twenty years ago, and researchers first used mRNA packaged in liposomes to transfect cells way back in 1989.

 

Amidst rapid visible progress it is easy to lose sight of the fact that much research goes nowhere very slowly. Even when successful, it might take decades to help patients. As Austin concludes, “only by advancing our common understanding of the complexity of translation, translational research and translational science will translational gaps be narrowed and eventually eliminated.”

Poll results: affiliation and fragment-finding methods in 2019

The fourth iteration of our fragment-finding methods poll has just closed. If you want to jump right to the results feel free to skip the next paragraph, which focuses on methods.

The poll was run using Crowdsignal, the successor to Polldaddy, and ran from 20 October through 30 November. This free polling software tabulates total number of votes for a question but not the number of individual respondents. To determine individual respondents, we included a question on “workplace and practice.” Of the 137 individual respondents to this question, 116 identified themselves as practicing FBLD, and we assumed they also answered the second question. The overall number of responses is slightly higher than in 2013 but a bit lower than in 2016.

Readership demographics have shifted from previous years, with about two thirds of respondents hailing from industry, up from just over half historically. The fraction of respondents who actively practice FBLD is also up modestly, to 85%.

But the question probably of most interest is on screening methods, summarized here.

As we also saw in 2013 and 2016, nearly all fragment-finding techniques are being used more, with the average respondent employing 6 methods today compared with 4.1 in 2016, 3.6 in 2013, and 2.4 in 2011.

X-ray crystallography has leapt to first place, likely driven in part by increasing speed and automation as well as by studies suggesting that crystallography can give impressively high hit rates.

As in 2016, ligand-detected NMR, SPR, and thermal shift assays are all very popular. Use of computational approaches has increased, though perhaps not as much as might be expected given recent advances. Functional screening is the only technique for which use has remained constant, or perhaps even declined very slightly from 2013.

For the first time we asked about use of literature to identify fragments, and nearly a third of respondents said they incorporate previously published fragments into their work. As the amount of publicly available information continues to increase it will be interesting to see whether this number grows.

More niche methods such as mass spectrometry, MST, affinity selection, and biolayer interferometry are gaining adherents; 30 respondents reported using mass spectrometry, for example. While fewer than 20% of respondents are using affinity chromatography (including WAC), CE, or ultrafiltration, that proportion has nearly quadrupled from our previous three polls, though we can’t say which of these related methods accounts for the increase.

Finally, only four respondents reported using “other” methods, such as SHG. Perhaps we’ll ask about this and other emerging methods explicitly next time.

Do the results surprise you, or are they consistent with what you are using at your organization?

New poll: affiliations and methods

It has been three years since we last asked about fragment-finding methods, and a lot can change in that time – just compare the world today to the world in 2016. Our new poll has two questions (right-hand side, under Links of Utility). Please answer the first, and answer the second if you practice FBLD.

The first question asks your affiliation and whether you actively practice FBLD or whether you are interested in the topic (though hopefully the latter also applies to the former!) We’ve simplified the question from prior years to include just four categories: For-profit practice, For-profit interest, Non-profit practice, and Non-profit interest. For-profit includes pharma and biotech as well as venture capital and consulting. Non-profit includes academia, government labs, disease foundations, and retirement.

Please answer this question as it is the only way we can count the number of respondents, which is essential for determining how many fragment-finding methods people are using on average.

If you do practice FBLD, the next question asks which method(s) you use to find and validate fragments. Please click every method you use, whether as a primary screening technique or for validation. You can read about these methods below, and if you select “other” please describe in the comments.

• Affinity chromatography, capillary electrophoresis, or ultrafiltration
• BLI (biolayer interfermotry)
• Computational screening
• Functional screening (high concentration biochemical, FRET, cell-based, etc.)
• ITC (isothermal titration calorimetry)
• Literature or known fragments
• MS (mass spectrometry)
• MST (microscale thermophoresis)
• NMR – ligand detected
• NMR – protein detected
• SPR (surface plasmon resonance)
• Thermal shift (or DSF)
• X-ray crystallography
• Other

Please forward this so we can get as many responses as possible.

Let the voting begin!

Poll results: affiliation, metrics, and fragment-finding methods

The latest poll has just closed, and the results are quite interesting – I’ll get to these in the next paragraph. First, a quick note on methodology. The poll ran from August 27 through September 30. Due to issues with polling in Blogger, we began running polls in Polldaddy in 2013; its interface gives the total number of votes for a question but not the number of individual respondents. Thus, for the questions on metrics and methods, I assumed that the number of respondents was equal to the number of people who identified themselves as practicing FBLD in the first question, or 123 out of a total of 154. The true percentages for the metrics and methods that people use could be higher or lower if not everyone answered all the questions.

Readership demographics have been remarkably stable since 2010 and 2013, with just over half of respondents from industry, and around 80% of all respondents actively practicing FBLD.

The next question asked about screening methods, and here things get more interesting.

The first thing to notice is that, as we also saw in 2013, nearly all fragment-finding techniques are being used more, with the average user employing 4.1 distinct methods today compared with 3.6 in 2013 and 2.4 in 2011. Ligand-detected NMR has jumped to first place in terms of popularity, with SPR and X-ray crystallography tied for second, followed closely by thermal shift. MST, while still in the minority, has had the largest percentage increase. The use of crystallography has certainly jumped since 2011, which fits with recent publications.

Finally, with regards to metrics, ligand efficiency (LE) continues to dominate, followed by LLE (or LipE), though overall usage of both is down compared with 2014. Only one of the other metrics broke the 10% mark. 

Again, if some practitioners answered the first question of the poll, but not the next two, the use of all methods and metrics could be underestimated. Still, these results seem to fit with what I’ve heard talking with folks – any surprises?

2016 polls!

We're heading into election season here in the United States, which reminds us that we haven't run any polls recently at Practical Fragments. How has the community changed in the past few years? To find out, please answer the three questions in the poll on the right-hand side of the page, under "Editors." Also, please note that you need to hit "vote" for each question separately.

The first question asks whether you are in academia or industry and whether you practice FBLD.

The second question asks what methods you use to find fragments. For purposes of this poll please choose all that apply, whether primary or secondary screens. You can read about these methods in the following links.

Affinity chromatography, capillary electrophoresis, or ultrafiltration
BLI (biolayer interfermotry)
Computational screening
Functional screening (high concentration biochemical, FRET, etc.)
ITC (isothermal titration calorimetry)
MS (mass spectrometry)
MST (microscale thermophoresis)
NMR – ligand detected
NMR – protein detected
SPR (surface plasmon resonance)
Thermal shift assay (or DSF)
X-ray crystallography
Other – please specify in comments

The third question asks what metrics (listed below) you use. Again, you can choose multiple answers.

Antibacterial efficiency
BEI (binding efficiency index)
Enthalpic efficiency 
FQ (fit quality)
Fsp3
GE (group efficiency)
LE (ligand efficiency)
LELP (ligand-efficiency-dependent lipophilicity)
LLE or LipE (ligand lipophilic efficiency)
LLEAT
%LE
PEI (percentage efficiency index)
SEI (surface-binding efficiency index)
SILE (size-independent ligand efficiency)
Other
None

Finally, are there other topics you'd like to see polled? Please let us know in the comments.

Poll results: affiliation, fragment-finding methods, and library size

Here’s a summary of the latest poll.

Readership demographics have not changed significantly since 2010, aside from a slight shift towards industry (~58% today vs 51% in 2010).

The next question asked about screening methods, and here things get more interesting.

The first thing to notice is that, with one minor exception, most fragment-finding techniques are being used more, with SPR and ligand-detected NMR now being used by more than half of all respondents. As a consequence, the average number of techniques being used jumped from 2.4 in 2011 to 3.6 in 2013.

The overall order of popularity doesn’t seem to have changed much, the major exception being X-ray crystallography, which is way up. However, this may be an artifact; a comment on the 2011 poll suggested that some voters interpreted the question to be about primary screening methods, as opposed to all methods.

(Technical disclosure: feel free to skip this paragraph unless you’re a data geek. Due to issues with polling in Blogger, this year’s poll was run in Polldaddy, the free version of which gave total votes for this question but not the number of individual respondents. However, since the two other questions in the poll allowed only single answers, the number of responses was equal to the number of respondents: 95 for the demographic question and 97 for the library question below. I thus assumed 97 respondents for this question, which is coincidentally identical to the number in 2011. Note also that the categories BLI and MST were new for 2013.)

Finally, the question on fragment library size shows that most folks are using libraries of 1000-2000 fragments, with only ~10% of respondents using very small (≤500) or very large (≥5000) collections of fragments.

This result is strikingly similar to the median of 1300 fragments that Jamie Simpson, Martin Scanlon, and colleagues found in an analysis of 22 published libraries. Teddy’s notes from FBLD 2012 put the median slightly higher: around 2500 for 17 libraries. Perhaps people with larger libraries tend to broadcast their size? Of course, in the end, it’s not the size of your library that matters; it’s what’s in it, and what you do with it.

Thanks again for participating, and if you have ideas for new polls, please let us know.

Updated polls: affiliation, methods, and library size

Practical Fragments has run polls on topics including readership, screening methods, favorite metrics (here and here), maximum and minimum fragment size, and the importance of structural information.

We’re interested in how things are changing, particularly in terms of our readership (last polled in 2010) and what fragment-finding methods are most popular (last polled in 2011).

Also, one topic that comes up repeatedly (for example here and here) but has never been actually polled is how many fragments make a good library – we’ve added a question about that too.

Please add your input for 2013; the more people who vote, the more representative the numbers will be. You can find all three questions on the right side of the page, below the "Links of Utility".

We’ll summarize the results and compare them to the previous polls in an upcoming post.

Also, please let us know if you would like us to repeat any of our other polls, and feel free to suggest new topics.

Happy voting!

Metallophilic fragments

A post earlier this month mentioned matrix-metalloproteinases (MMPs). Now, a recent issue of J. Am. Chem. Soc. carries a Communication about fragment-libraries designed for zinc proteases, of which MMPs are a subset.

Seth Cohen and coworkers at University of California San Diego and the Weizmann Institute of Science in Israel designed two libraries based on known zinc chelators: quinoline sulfonamides (QSL) and benzimidazole sulfonamides (BISL) (see Figure). They rapidly assembled 40 of the former and 37 of the later using microwave chemistry and tested these against a handful of different MMPs.

Both libraries produced hits against MMP-2, MMP-3, MMP-8, and MMP-9. Control compounds designed not to chelate zinc showed no activity, and X-ray adsorption fine structure spectroscopy experiments suggest that the molecules are indeed binding to the catalytic zinc. Selectivity is often an issue in targeting metalloproteinases, and it was thus gratifying to find that at least one fragment inhibited MMP-2 with low micromolar activity while showing no activity against the other MMPs. Molecular modeling provides some rationale for this selectivity.

One could argue that many of the library members do not meet conventional definitions of fragments, and could be seen as more scaffold-like (or worse – one has a molecular weight pushing 600 Daltons!) And of course, it is not clear that either scaffold will be suitable for drug development or even tool compounds – it is possible their propensity for zinc binding will be a problem inside cells. Still, the notion of creating custom-made fragment libraries for various classes of targets certainly makes sense; folks have done this for kinases and even RNA, and it is reasonable to see this approach extended to metalloproteinases. Cohen and colleagues described a fragment library consisting of more conventional metal chelators earlier this year in ChemMedChem.

This publication also confirms the results of our poll that fragment-based approaches are catching on in academia. But industry is already in the sandbox: at least two companies, AnCore and Viamet, are using similar strategies to target metalloproteins.

Poll results: academia/industry

Just a quick summary of our poll last month. The results (below and to right) show that just over half of you who responded (51%) are in industry and just under half (46%) are in academia, government, or other non-profit organizations. Also, over three-quarters of you (77%) are active practitioners of FBDD.

Thanks to everyone (over four score) who took the time to respond!

Poll: academia/industry

It’s been a while since we’ve done a poll, but the latest post at FBDD-Lit on fragments in academia, combined with an earlier post on this site, leads us to wonder how many of our readers are from academia and how many are from industry. (For purposes of this poll, let’s lump government and other non-profit organizations with academia).

Please respond by clicking on the right-hand side of the page – we’d like to know more about you!

“The Hidden Pool” revisited

Last year, in response to a post by Teddy on whether there is a “hidden pool” of FBDD practitioners being trained in academia, guest blogger Derren Begley suggested that for the most part fragment-based approaches are restricted to industry: in universities “there are ‘puddles’ of FBDD here and there, but not what I would call a vast resource.” I think this statement was true at the time, but may now be changing. For example, Practical Fragments' last four posts have all covered papers that came out of academia.

There also seems to be an increasing trend of industrial scientists moving to academia, driven by factors ranging from the decreasing number of jobs in industry to the increased freedom in academia. These moves span the gamut, from world-class scientists leading entire departments to folks coming in as assistant professors, staff scientists, and research associates. But they are bringing their interest in fragments with them. In fact, of the last four blog posts mentioned, at least two involved people with current or former industry ties.

Finally, there seems to be increasing academic interest in fragments. I’ve given a couple talks in the past two months at Carnegie Mellon – University of Pittsburgh and St. Jude Children’s Research Hospital, and Peter Kenny has spent the past year as an itinerant fragment evangelist at universities around the world. I know that St. Jude in particular is actively seeking someone with an interest in FBDD, and with resources comparable to what you would find in big-pharma, they make a pretty appealing destination.

What are you seeing? Is FBDD going ivory?