ChEMBL

The identity of compounds in the literature is often uncertain - with high profile cases of incorrect compounds being used in experiments - with subsequent difficulties in reconciling conflicting experiments or repeating results.

One example is the kinase inhibitor Bosutinib (SKI-606) - where several compound vendors shipped a similar isomer of the actual drug. It will be unclear which data comes from the bona fide Bosutinib and the compound sold as Bosutinib by multiple vendors. More details on this case are in this post by Derek Lowe, and there is a definitive structural biology paper here. So this probably clouds a lot of the reported Bosutinib bioactivity data that's out there. Here the difference is in the differential substitution pattern on an aromatic ring (2,4-dichloro-5-methoxy vs 3,5-dichloro-4-methoxy), the mass is the same for these isomers.

A second example is this case (a clinical stage compound called TIC10) where there was a mix-up in the structure assigned to a compound in a patent, and since the substance had novel and potentially useful bioactivity and the annotated structure in wrong, led to all sorts of complicated IP issues and shenanigans. Since this compound was also in a widely distributed and profiled NCI set, then the literature ends up with difficult to deconvolute data.

There are probably many of these examples - and here are two more, both connected to clinical development stage protein kinase inhibitors from Exelixis.


The first is XL-765 also known as SAR-245409 and by the INN Voxtalisib - it is a PI3K inhibitor. Compound vendors have been selling 'XL-765' for some time, but the structure sold is (typically) not the correct XL-765 structure.

XL-765 is known to be this structure - multiple independent authoritative source point to this identity. It's a quite simple, small molecule.  The InChI key is RGHYDLZMTYDBDT-UHFFFAOYSA-N.
Several vendors have been selling a different structure as 'XL-765/SAR-245409'; as you will immediately note, it is a very different structure - not a positional or stereo-isomer, it will have very different mass, etc.



Some purchasers of this compound report peer-reviewed in vivo data. To be clear, this isn't just one company, it is all/most vendors of XL-765.


So there are a number of things that could have happened here:

i) The correct structure was supplied, but the structure on the label/on the website didn't match the real physical structure - i.e. a mislabelling.
ii) The incorrect structure was supplied, and the structure on the label/website was what was in the bottle. In our studies (at FIMM) the vendor supplied XL-765 has not behaved as a PI3K inhibitor, so the latter is more likely.

However, the incorrect XL-765 structure has propagated into public chemistry databases, and literature data for XL-765 is probably now largely suspect (with the exception of that from Exelixis themselves (and their collaborators)).

Here's the second new example - XL-147 (aka SAR-245408 and Pilaralisib) - again a PI3K inhibitor. The correct structure is QINPEPAQOBZPOF-UHFFFAOYSA-N.

Many vendors were selling XL-147 as the following compound, here there is a lot more similarity between the actual and sold compound, but it's still different, and any biology on this, although it may well be active in it's own right, is not the same as XL-147.



tl;dr Be careful if you are interested in purchasing or analysing activities and properties of Bosutinib, Pilaralisib &Voxtalisib. Be careful in loading names from Vendor catalogs, and try to use more definitive authorities for compound synonyms. Be careful with relying on things from any public databases.


Krister and I would like to thank Willie Yuan at Chemietek for helping to clarifying aspects of the confusing history for this compound.

jpo and Krister