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

• Published in: Journal of medicinal chemistry 2015-02, Vol.58 (3), p.1205-1214
• Main Authors: Devine, Shane M, Mulcair, Mark D, Debono, Cael O, Leung, Eleanor W. W, Nissink, J. Willem M, Lim, San Sui, Chandrashekaran, Indu R, Vazirani, Mansha, Mohanty, Biswaranjan, Simpson, Jamie S, Baell, Jonathan B, Scammells, Peter J, Norton, Raymond S, Scanlon, Martin J
• Format: Article
• Language: English
• Subjects: Drug Discovery; High-Throughput Screening Assays; Magnetic Resonance Spectroscopy; Molecular Structure; Surface Plasmon Resonance; Thiazoles - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501402x

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.