MDM2-p53 protein-protein interaction inhibitors

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.

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6 Responses to MDM2-p53 protein-protein interaction inhibitors

  1. milkshake says:

    Nitro is notoriously hard to replace with an isoster – there are not too many small FGs that can have bot strong H-bond accepting ability and strong el-withdrawing effect on the benzene ring. Nitro replacement with a halogen, cyano, carboxamide or sulfoxide often leads to order-of-magnitude drop in potency. I think one of the under-used nitrophenyl isosters is 3,4-benzo-1,2,5-oxadiazole. It is very easy to make from o-nitroaniline or 2-fluoronitrobenzene and it has pretty nearly the same shape, H-accepting properties and el-deficient benzene ring like nitro. And it is metabolically stable and often improves patentability. The only problem is that small-MW benzooxadiazole building blocks are potentially explosive (on the same level of low shock sensitivity as TNT) which makes process folks apprehensive. But I have seen few papers with benzoxadiazoles though none in an approved drug yet.

    I think dangers of nitro group are vastly over-rated, it is from the cover-the ass category of concern, especially if the compounds are given in extremely low dose, or if they are used as anticancer compound, or in an antibiotics. You can see nitro groups in old approved drugs quite frequently, even in drugs used long term on daily basis like nifedipine.

    Nitrobenzenes get metabolized to aryl hydroxylamines which are nasty, but there are other commonly used pieces with just as bad tox metabolite liability, ie. electron deficient naphtalenes and thiophenes which many chemists hardly know about, as the duloxetine problems show quite clearly. But everybody heard that nitro = a poison.

    • milkshake says:

      I intended to write “electron-donating group substituted naphthalenes and thiophenes” actually, as an examples of pieces with serious metabolic liability, apt at producing electrophilic species unpredictably. Sorry for the typo

  2. mcbcm says:

    Milkshake, you raise an interesting point about nitro groups. Certainly most medicinal chemists choose to steer clear of them but probably not based on personal experience. I have accumulated quite a list of groups I would rather not include in a molecule over my relatively short career – based on friendly advice from more experienced colleagues, often backed up by a horror story from the clinic. What is more difficult is sifting through this advice and sorting out the genuine horrors from the less problematic. Personally, I am happier when I know I have an assay early in my cascade that can test whether a group is bringing a problem than when the risk is only likely to become apparent later down the line.

  3. milkshake says:

    yeah, the assays like Ames are actually quite expensive and could be misleading – so typically you don’t get to use them to screen out potential problems early enough. And metabolic activation that produces electrophilic nasties could be a sporadic serious complication that surfaces only in phase III after enough patients get enrolled (few of which happen to have a wrong variant of CYPs or some unexplained quirk of immune system that makes them prone to a bad reaction). In absence of firm knowledge about the tox potential people become circumspect and super-conservative – and it is easy to go overboard and throw out good stuff on mere suspicion. Of course one never knows what was missed based on the suspicion, and what could have been – so there is no learning based on feedback and the doctrines about what is permissible in a molecule are repeated and passed on.

    I heard that certain large companies had bad experience with tox related to anilines. So it became an official policy to avoid any aniline in the molecule and even any group liable to produce aniline, like acetamino group. This is in my opinion completely overboard because the two most common types of aniline electrophilic metabolites, quinones/quinonimines and N-aryl hydroxylamines form only from electron rich anilines. Electron deficient ones do not have this problem, so in such case to have a carboxylic acid on the ring, or replace the benzene ring with pyridine and the aniline tox problem may go away. (In old times when p-aminosalicylic acid was used to treat TB, the medical textbooks recommended dosing 15-20 grams a day, saying that doses below 10g/day are considered ineffective. Even electron rich acetanilides that do form reactive quinonimines are not alway horribly toxic, as the experience with Tylenol shows, but O-methylated Tylenol analog actually did cause kidney cancer in patients.

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