The thousandth Practical Fragments post!

As the title states, this is the 1000^th post at Practical Fragments. This blog was conceived in 2008 over drinks at the Third Annual CHI Fragment-based Drug Discovery Conference. (Don’t miss the twentieth in April!) Teddy Zartler said he was planning on starting a blog and asked if I wanted to join. In July of 2008 Teddy wrote the first post, and every month since then has seen at least a couple new ones. I thought it would be fun to look back briefly on the past 16+ years.

 

Methods

The very first Practical Fragments post asked what screening methods people use, and this eventually led to five polls on the topic, the latest of which published just a few months ago. In our first formal poll, in 2011, the average respondent used 2.4 techniques. Today that number has grown to 5 due to the increased recognition that different methods have different strengths and weaknesses.

 

By far the biggest winner among methods has been X-ray crystallography; it jumped from sixth place in 2011 to first place in both 2019 and 2024. Crystal structures have long been prized in drug discovery, but the dramatic increases in throughput and automation over the last decade mean more structures are more available to more users.

 

Computational methods too have improved spectacularly. In 2009 we highlighted an in silico screen of around 67,000 fragments which yielded ten micromolar inhibitors. Today, screening multibillion compound libraries is becoming routine, and artificial intelligence is likely to enable even more opportunities.

 

Pitfalls

One of the reasons that it took so long for FBLD to develop was the myriad artifacts that can haunt screens run at high concentrations. For example, compound aggregation was not widely recognized until the first decade of this century, and even today too many papers are published without checking for this pathological phenomenon.

 

Similarly, pan-assay interference compounds, or PAINS, were not defined until 2010. Scientists at large companies have long known to steer clear of certain chemotypes. Now academics and folks in startups are more aware of problematic substructures, even if Dr. Saysno objects.

 

Long-time readers may recall a series of posts on “PAINS-shaming,” where we highlighted (lowlighted?) papers that lacked appropriate selectivity or mechanistic studies. Occasionally this led to productive discussions, as in this example where an author and journal editor contributed to the comments. But with the increasing use of metrics measuring social media engagement to rank articles I’ve decided that blogging about them may inadvertently reward shoddy science. If you’re looking for most of the things that can go wrong in a screen, check out this open-access review by Ben Davis and me.

 

Covalent craze

One prominent mechanism of PAINS is indiscriminate covalent modification of proteins. For many years drug hunters actively avoided covalent modifiers for fear of off-target modifications and their potentially toxic effects. Indeed, the first several mentions of covalent compounds at Practical Fragments were in the “things to avoid” category. We discussed reversible covalent modifiers in 2012 and 2013, but it wasn’t until 2014 that we wrote about intentionally irreversible fragments.

 

How times have changed! The success and safety of targeted covalent kinase inhibitors has fueled enthusiasm for covalent drugs in general, creating opportunities for fragment-based approaches. Indeed, as we discussed here, both reversible and irreversible fragment-based screens were used in the discovery of the first approved drug targeting the previously intractable target KRAS, and these learnings have been applied at multiple companies to produce an impressive armamentarium against what Darryl McConnell has called “the beating heart of cancer.”

 

To find KRAS inhibitors, researchers screened pure proteins against libraries of covalent fragments. One of the most exciting recent developments in chemoproteomics has been screening covalent fragment libraries in intact cells or cell lysates to find hits against thousands of proteins in their native environment. We first wrote about this approach in 2016, and last year we highlighted the first drug to enter the clinic from covalent screening in cells.

 

And all this is just the beginning: each of our past four annual “review of reviews” posts has featured between three and six papers focused on covalent fragment-based drug discovery.

 

Clinical compounds

My first blog post in 2008 was a brief mention of a C&EN story on FBLD, in which I noted that “an FBLD drug that reaches the market by 2011 would be a ‘psychological’ victory for the whole FBLD community.” Although I claim no prescience, I was happy to see vemurafenib approved in August of 2011.

 

Indeed, I would argue that FBLD-derived drugs are the most meaningful output and validation of the field. Our first systematic tabulation in 2009 counted just 17 that had entered clinical trials, and today there are more than 60. Like investigational drugs in general, the majority of these have stumbled, but at least eight have been approved by the US FDA, and more are working their way through clinical trials. While eight might seem like a modest number, the number of patients they’ve helped is orders of magnitude greater.

 

Closing thoughts

There are far more themes in a thousand posts than I could summarize in a single one: metrics, induced proximity, and newer methods such as cryo-EM all come to mind. But as this post has already surpassed 1000 words, I’ll wrap it up.

 

One minor frustration has been the sparsity of comments; it sometimes feels as if I’m blogging into the void. That said, I’m pleased that some posts may have led to new research, such as this. And blogging can be its own reward: I sometimes find myself using the “Search This Blog” function on the top right-side of the page when I’m trying to remember a paper from years ago.

 

Since Teddy left the FBLD field several years ago I’ve been writing most of the content, with occasional guest posts (such as this from Glyn Williams). At the current rate it might take a couple decades for Practical Fragments to reach 2000 posts, if we even get there. But for now, I’d like to thank each of you for reading. I hope you enjoy it and that is has, at least occasionally, made your scientific pursuits more practical.