Porter’s Papers – A review of recent literature from Rod Porter

(Full text of Rod’s bi-monthly newsletters, which include med chem literature reviews in addition to the more general/comp chem papers included here, can be found on his website at http://rodporterconsultancy.com/newsletter/)

Molecular properties and in vitro and in vivo toxicology and disposition

An important contribution from the group at Lilly 1 outlining their analysis of physicochemical and ADMET properties with PK and toxicology data on some 3,773 compounds from 173 different chemical classes. Firstly the authors provide a critique of the numerous previous studies which have analysed physicochemical properties of compounds in relation to toxicology or surrogates of toxicology readouts pointing out the lack of consideration in many of covariants for example the relationship between solubility and molecular weight should also perhaps consider the impact of ionisation or lipophilicity as well.

The study highlighted the importance of rat in vitro hepatocyte toxicity combined with volume of distribution for in vivo toxicology (LOAEL based on histology or death) outcomes and microsomal clearance with cLogP for predicting unbound clearance. Higher clearance looked like bad news for toxicology as well all of which tends to make intuitive sense but now with a sense of quantitation. Indicators of oral bioavailability were weak – decreasing PSA or increasing solubility gave modesteffects on improving bioavailability with permeability also only having a minor impact

Further work was done to look at the effects of single point changes in structure, however within the constraints of the data set there were not too many surprises. Having said that I did find it a little surprising that replacing a CF3 with F gave an increase in LOAEL and replacing F with H gave a further increase although as the authors admit the sample sets were small. I also found the observation that Vdss is reduced going from a nitrile to a methyl group but I suspect here that context is all as this is looking at the point substitutions in isolation and ignoring long range electronic effects. I think this is a valuable paper particularly with its focus on toxicology outcomes but taking a slightly different approach to the Pfizer groups analysis 2 of their tox data.

1.      J.J. Sutherland et al, J. med. Chem. 2012, 55, 6455

2.      J. D. Hughes et al, Bioorg. Med. Chem. Lett., 2008, 18, 4872

Managing PPI’s

Protein-protein interactions are being seen increasingly as attractive albeit tough targets. PPI’s vary from clefts much like a ligand-protein binding site through to large fairly flat systems perhaps with a few binding hotspots. Generally success has been achieved in targeting the former and not the latter. In a recent review 1 the authors summarise the approaches that might be taken to address the latter targets in particular. Strategies discussed include allosterism and intervening in post translational modifications. Nature can also provide inspiration, cited for example, is the role of vinblastin in microtubule destabilisation. This is a short review but for those of you interested in PPI’s a useful summary. I guess in a similar vein a paper 2 from a group at Genentech discusses RAS inhibition via direct RAS binding by compounds – a number of agents are known that show activity although affinities are generally low e, g (1), (2). The authors highlight the challenge is now to increase the activity of these compounds and selectivity particularly with respect to other GTPases.

A recent paper 3 discusses the use of virtual screening to identify inhibitors of the JNK-JIP1 interaction. This has been an active area of research with a number of inhibitors identified. The authors used one of these inhibitors BI-78D3 to identify in silico where it may bind to JNK and a putative bound conformation using the crystallographic data for the JNK-JIP1 interaction. A virtual screen of the NCI Diversity Set generated a number of hits which gave IC50’s for displacement of JIP from JNK of between 0.7 and 22uM. Not a perfect story perhaps but a demonstration that “conventional” techniques have value for PPI’s when appropriately used.

1.      A. Thompson, et al, ACS Chem. Biol., Article ASAP, DOI: 10.1021/cb300255p Publication Date (Web): July 23, 2012

2.      W. Wang et al, Bioorg. Med. Chem. Lett., 2012, 22, 5766

3.      T. S. Kaoud et al, Med. Chem. Lett., Article ASAP DOI: 10.1021/ml300129b Publication Date (Web): August 13, 2012


So far so not so good – 2012

Just noted 1 that for the first two quarters of 2012 there have been 12 new FDA drug approvals (NCE and biologics) this compares with 30 at the same stage last year. Two of the approvals this year were the two anti-obesity drugs – not exactly new compounds bearing in mind how long it took them to get approval. So the article I rerviewed last time talking about 2015 as perhaps crunch tiime when the reduced PhI pipeline catches up with launches perhaps looked a little optimistic.

1.      L. DeFrancesco Nature Biotechnology 2012, 30, 817



Learning lessons

A short article from Richard Elliott at the Gates Foundation suggesting some lessons that pharma can learn from those working on neglected diseases – disease areas working in a lean business environment. Briefly they are

  • Go for compounds not targets that is advocating phenotypic screening – broadly hard to argue with except there are major areas of unmet medical need such as CNS where phenotypic screening can be tough.
  • Consider compound libraries as pre-competitive, the IP tends to be found in what was done after the hit was identified.
  • Be open minded – citing Lipinski as an example of guidelines that became unbreakable rules.
  • Have a long term strategy and stick with it – now that would be nice!

I guess we could all add few more items to this list.

1.      R. L. Elliott ACS Med. Chem. Lett., Article ASAP DOI: 10.1021/ml3002105


Why we are here

As a research worker it can be easy to get a little detached from why you spending ludicrous hours working on a particular problem – or lets face it a small part of a larger problem when it comes to drug discovery. I thought this article 1 was a timely reminder of the importance of reminding ourselves why we got into our chosen career. Very simply it is the story of a graduate student who organized a meeting of people affecting by Alzheimers disease, patients, carers, and research workers. Bottom line of this was that not only were the researchers re-enthused for their work but the patient/care group benefited enormously as well. As the author pointed out patient communities spend a lot of time raising money for research and the researchers spend most hours of the day trying to discover treatments but direct contact is rare. Its only a page long but worth a read.

1.      T. Nuriel Nature 2012, 487, 7