To date, a number of tool compounds have been generated at the LDDN. One example, is from the UCH-L1 (ubiquitin C-terminal hydrolase L1) inhibitor program. The LDDN developed a high-throughput UCH-L1 enzymatic assay, which targeted acyl enzyme formation. Screening of the LDDN library identified multiple series of compounds including the isatins (e.g., 1), with weak UCH-L1 inhibition and low selectivity for UCH-L3. Through medicinal chemistry modification, the lead compounds were further refined to enhance potency and selectivity. Following the optimization, compound 2 (LDN-0057444) was identified as a potent and selective UCH-L1 inhibitor. Following four publications by the LDDN, two compounds became commercially available (LDN-0057444 and LDN-0091946), and these have become the primary tool compounds used by researchers in both academia and industry for elucidating the role of UCH-L1 activity in cancer, Parkinson’s Disease, and other neurological disorders.
Leading references on LDN-0057444 and LDN-0091946 include:
Liu et al (2003) Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem. Biol. 10 837.
Love et al (2007) Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nature Chemical Biology. 3 697.
Tan et al (2008) Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. Mol. Cell. Biochem. 318 109.
Cartier et al (2009) Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1. J. Neurosci. 29 7857.
Zhang et al. (2012) Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J. Neurochem. 120 1129.Martinez-Villarreal et al (2012) Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination. Glia. 60 1356.