The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have what type of enzyme inhibition can be reversed been demonstrated to inhibit cellular DUB activity.
We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well. In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft. Phe182 residue on the WPD loop. The phosphatase activity of PTP1B occurs via a two-step mechanism. Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack. Arrow pushing mechanism of PTP1B phosphatase activity.
Two step mechanism of PTP1B phosphatase activity. This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind. Phosphprylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive. Although PTP1B is generally high liver enzymes in older cats as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B.
Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer”. The two faces of PTP1B in cancer”. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis”. Effect of temperature on enzyme activity salivary amylase nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence”.