Discovery of 2‑(Cyclohexylmethylamino)pyrimidines as a New Class of Reversible Valosine Containing Protein Inhibitors

Valosine-containing
protein (VCP), also known as p97 or cdc48 in
yeast, is a highly abundant protein belonging to the AAA ATPase family
involved in a number of essential cellular functions, including ubiquitin–proteasome
mediated protein degradation, Golgi reassembly, transcription activation,
and cell cycle control. Altered expression of VCP has been detected
in many cancer types sometimes associated with poor prognosis. Furthermore,
VCP mutations are causative of some neurodegenerative disorders. In
this paper we report the discovery, synthesis, and structure–activity
relationships of substituted 2-aminopyrimidines, representing a new
class of reversible VCP inhibitors. This class of compounds, identified
in a HTS campaign against recombinant VCP, has been progressively
expanded and manipulated to increase biochemical potency and gain
cellular activity.