When my parents were young and just starting out (the late 60s) they needed a vacuum cleaner. So a vacuum cleaner salesman came to the house eager to make the sale. This was the era of the Space Race, plastics, and so on. So, it was cool to be associated with this. The eager young vacuum cleaner salesman showed my parents the fine, sleek design of the vacuum cleaner (it was a ELECTROLUX). It was long and sleek, looking like a rocketship (or a dachshund). It came with a lot of nozzle attachments. One in particular was shaped to be very narrow, and get in between the couch and wall for example. He was particularly proud of this piece: the AEROspace tool. He even wrote it down as such. You must have a "AEROspace" tool for your vacuum. It was an example of great marketing, associate yourself with something very popular to make something mundane appear special.
So, this paper comes along from Moffatt Cancer Center and USF targeting ACK1 (aka TNK2). This paper purports to have a "innovative fragment approach" (mix and match). I love novel approaches to libraries. So, let's dive in. There is a good deal of work that has been done with ACK1 by Amgen, OSI/Astellas, and others. Dasatinib and Bosutinib also show activity against ACK1 also. Based upon all of this previous work and the knowledge of the pyrimidine core they decided to approach the target as laid out in Figure 1.
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| Figure 1. Library Design Approach |
So, this paper doesn't interest me, although they do come up with some potent compounds, from a what they discovered aspect, rather from a more philosophical aspect. What does it mean to do fragments? This harkens back to the Safran Zunft challenge. To me, FBDD is about using simple, small molecules. Pyrimidine series 9 does not fit any definition of a fragment (Cpd 8 would, but it was never tested AFAIK). What they did was identify a variety of fragments which would be inputs for creating a small library of lead-like compounds. However, for this to be "Fragment-based" I would think that they would tested each individual component and prioritized chemistry based upon that. Or maybe they could have made R3=H. They don't report Ligand Efficiencies (cue Pete Kenny). This is simply not "Fragment-based" anything. Nor, do I think this approach is novel. Nor do they explain how this is novel.
So, I think we have entered the time when anything that uses a fragment in the design process is fragment based. Based on this line of thinking, Nicolaou's total synthesis of Taxol is "Fragment-based". Beware those talking the talk, but not walking the walk.
I can't see the article (and don't feel especially deprived by this) and this seems to be a hybridization approach which people have been doing for years. Probably more accurate to describe the design as 'modular' than 'fragment-based' because relevant groups are not assayed (or even docked) as fragments. When doing this sort of thing one should be particularly alert to the possibility of non-additivity in the SAR.
ReplyDeleteOn the other hand, having been in this field for as long as I have, it is kind of nice to see fragments used as a selling point, rather than something hidden away in the basement and discussed only in whispers.
ReplyDeleteThat said, the word "novel" comes up 10 times in the text of the article, and another 4 times in the references - seems like novelty is quite common!
Another pretty shitty aspect of this paper is that 2,4-diaminopyrimidines with a small substituent in 5 position are so promiscuos that when explored in combichem fashion (for which they are ideal since the 4 subsitution is much faster than 2 substitution) they are 100% guaranteed to provide high potency kinase inhibitor, for any kinase that you wish. They obvious difficulty is that there is almost no selectivity against unrelated classes of kinases. So if one start from bis-aminosubstituted pyrimidine hit, there needs to be some serious X-ray based optimization work.
ReplyDeleteGee, back in the day, we would just call this "medicinal chemistry". And pretty rudimentary medicinal chemistry, at that. Like, sophomore-in-college-medicinal-chemistry.
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