PTP1B has been shown to pose attractive features as a potential drug target. Inhibition of PTP1B seems beneficial in adult-onset diabetes, obesity, and some forms of cancer, like breast cancer and colorectal carcinoma.
For the design of selective PTP1B inhibitors we use a given mechanism-based covalently modified target enzyme as the key player in the selection of fragments and in situ assembly (i.e., within PTP1B’s binding site) of its own lead inhibitor structures. Thus, the development of potent and selective small molecule inhibitors following this “covalent draft” strategy will be orchestrated by the covalently modified target enzyme, through the selection and attachment of additional weak binding fragments. The resulting “complex” will serve as inspiration for novel non-covalent ligands. In the first stage PTP1B will be covalently modified by a mechanism-based active probe.
This probe also includes an additional reactive group, inert to the protein’s functionality, that will react with its complementary partner, also biologically inert, which is presented by each one of the members of a fragment library pool. Thus, following a binding event a fragment will react with the enzyme-probe adduct to afford a covalent linkage. The mechanism–based probe constitutes the anchor point for the future inhibitor while the enzyme chosen fragment represents its selectivity factor. If necessary, additional fragments could also be introduced in a similar way. Following structural analysis the actual full-length inhibitor will be prepared using a transition state analog for the anchor point coupled, via the same coupling chemistry, to the chosen selectivity fragment. This strategy uses wild type enzymes without any structural preconditions. The leads resulting from this approach are expected to be both potent and selective for the templating enzyme target.