The successful development of inhibitors of protein-protein interactions remains a formidable challenge for medicinal chemists. An excellent review highlights some successes in this field and ascribes the low tractability of these targets to:
- The large contact surfaces between proteins (~1,500–3,000 Å2).
- The flat and relatively featureless nature of these surfaces as compared to the active-sites on more traditional targets.
- The lack of a natural small molecule ligand to use as a lead molecule.
However, as the authors go on to discuss, it is often found that a small number of amino acid residues contribute disproportionately to the binding interaction between proteins. Targeting these so-called hot-spots represents an approach to tackling these targets. The review provides a nice analysis of six examples of the successful discovery of inhibitors of protein-protein interactions.
Recently, scientists at the Universities of Newcastle and Oxford have published the optimisation of a series of isoindolinone inhibitors of the interaction between Murine Double Minute 2 (MDM2) and p53. The tumor suppressor protein p53 acts as a signalling node and is involved in the response of cells to a range of stresses. Inactivation of p53 is often involved in the development and subsequent progression of cancer. Inhibitors of the MDM2-p53 interaction have been proposed as anti cancer agents. The same team has previously reported isoindolinone 49 that has an IC50 for the MDM2-p53 interaction of 15.9 μM. This paper outlines the optimisation of this compound to generate 74a with an IC50 of 0.17 μM. Ideally the optimisation would have been supported by X-ray crystallography, however the team were unable to obtain co-crystals of the series bound to their target, the MDM2 protein. Instead a combination of NMR studies and docking were used to predict binding modes for the inhibitors.
Through the preparation and testing of analogues of 49 it was established that increases in potency were achievable through the introduction of a para nitro substituent on the N-benzyl group and by steric restriction of the 3-carbon chain through introduction of a cyclopropyl group. Despite considerable efforts to find a suitable replacement for the nitro-group the team were unable to find a similarly active replacement. Separation and testing of the enantiomers of 74 showed that the (R) form, 74a, is primarily responsible for the MDM2-p53 inhibition.
The authors go on to demonstrate cellular activity for 74a in a range of assays. This paper provides nice evidence of the inroads that medicinal chemists are making into the challenging protein-protein interaction target class.