Skip To Content

Bosutinib: A Case of What Could Have Been?

For many years I have been looking for a high profile public case that represents a good example of why an automated NMR structure verification system can help prevent bad things from happening. We all know these types of examples exist, but they don't generally become public knowledge. 

Yes, I've blogged about this topic many times over the  years. To name a few:

Back to Reality #1- LC/MS vs. NMR

The Realities of NMR in the New(ish) Discovery Environment

Are We There Yet? Automated Structure Verification (ASV)

The Black Swan of Compound Libraries

Recently, an article in C&E News was published. It can be read here:

Bosutinib Buyer Beware

In short, there appears to be a lot of bottles of bosutinib out there that actually contains the wrong isomer. 

Bosutunib is a tyrosine kinase inhibitor that Pfizer is hoping will be one of their next big drugs. Also known as SKI-606, it is currently in Phase III trials to treat chronic myeloid leukemia. 

Naturally, for such a high profile compound there are a fair amount of research groups who have been conducting their own studies on this compound. Problem is, there is a lot of the incorrect stuff floating around out there. The latest update on the PKC Pharmaceuticals, Inc. website have reported that up to 18 vendors have actively sold to one or more customers in the biochemical reagent marketplace, an incorrect bosutinib isomer.

Derek Lowe at In the Pipeline has also sounded off on the issue.

Naturally, the first thing that came to my mind when reading this story was, could an automated NMR software system have caught this mistake. From the C&E News article:

Levinson and Boxer put their publication on hold, ordered bosutinib from a different vendor, and did a battery of tests to determine which material was the genuine bosutinib. They soon figured out the original compound they had done all their research on turned out not to be bosutinib. “We had wasted a huge amount of time and money on the wrong isomer,” Boxer says.On the basis of multidimensional nuclear magnetic resonance (NMR) experiments, Boxer and Levinson believe that this isomer not only has a chlorine at the 3-position rather than the 2-position, but also that the chloro and methoxy groups that appear in the 4- and 5-positions, respectively, in bosutinib’s aniline moiety have been switched.The difference between the two molecules is subtle. Mass spectrometry and elemental analysis would be the same for both compounds. There are differences in the aromatic region of the 1H NMR, but one wouldn’t necessarily pick up on them unless they compared the two compounds side by side. It’s only when you use 13C NMR that the symmetrical nature of the aniline group in the isomer becomes clear.

 

Here are the two molecules in question:

4486102

Much of the discussion has been that the average chemist would let the incorrect isomer through with just the LC-MS information and quick glance at the 1H. Of course the 13C NMR would clearly point out the difference but this isn't standard practice for many bench chemists. 

But would one have even needed to acquire a 13C NMR spectrum for this?

Would a 1H NMR have been enough? At the very worst, a HSQC experiment? The supporting documentation for this article suggests clearly yes to the latter. 

Phil Keyes from Lexicon Pharmaceuticals and I are working on this right now and should have some results showing how our automated NMR verification system would have handled this case. 

More details to follow…stay tuned!