2 research outputs found
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
Alkylsulfanyl-1,2,4-triazoles, a New Class of Allosteric Valosine Containing Protein Inhibitors. Synthesis and Structure–Activity Relationships
Valosine containing protein (VCP), also known as p97,
is a member
of AAA ATPase family that is involved in several biological processes
and plays a central role in the ubiquitin-mediated degradation of
misfolded proteins. VCP is an ubiquitously expressed, highly abundant
protein and has been found overexpressed in many tumor types, sometimes
associated with poor prognosis. In this respect, VCP has recently
received a great deal of attention as a potential new target for cancer
therapy. In this paper, the discovery and structure–activity
relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent,
allosteric VCP inhibitors, are described. Medicinal chemistry manipulation
of compound <b>1</b>, identified via HTS, led to the discovery
of potent and selective inhibitors with submicromolar activity in
cells and clear mechanism of action at consistent doses. This represents
a first step toward a new class of potential anticancer agents