Promiscuous 2‑Aminothiazoles (PrATs): A Frequent Hitting Scaffold

We
have identified a class of molecules, known as 2-aminothiazoles
(2-ATs), as frequent-hitting fragments in biophysical binding assays.
This was exemplified by 4-phenylthiazol-2-amine being identified as
a hit in 14/14 screens against a diverse range of protein targets,
suggesting that this scaffold is a poor starting point for fragment-based
drug discovery. This prompted us to analyze this scaffold in the context
of an academic fragment library used for fragment-based drug discovery
(FBDD) and two larger compound libraries used for high-throughput
screening (HTS). This analysis revealed that such “promiscuous
2-aminothiazoles” (PrATs) behaved as frequent hitters under
both FBDD and HTS settings, although the problem was more pronounced
in the fragment-based studies. As 2-ATs are present in known drugs,
they cannot necessarily be deemed undesirable, but the combination
of their promiscuity and difficulties associated with optimizing them
into a lead compound makes them, in our opinion, poor scaffolds for
fragment libraries.