A-1331852

In vitro selectivity within the target family is good but no wider profiling is available. There are indications on target engagement based on knock-out experiments as measured by cell viability, but proof of direct in cell target engagement is lacking.

Targeting BCL´s with a small molecule is challenging. The interaction of Bcl-xL with A-1331852 in complex (PDB: 6VWC) should be added to the review form. There is a significant amount of data showing the activity of A-1331852 in a range of cell-lines and xenograft models (10.1126/scitranslmed.aaa4642). However, there is insufficient experimental data showing its overall profile against other protein targets. A search in PubChem for A-1331852 only yielded BioAssay Results for the BCL proteins. Therefore, the major concern with A-1331852 relates to its off-target affects against for example kinases, GPCRs, nuclear receptors, ion-channels, proteases, etc. Without such a comprehensive profile, the observations of A-1331852 in cell-based assays may be due its poly-pharmacology. Once such data is made available, A-1331852 is likely to meet the criteria for use as a Probe in cells.