The rule 2-0

Recently, Aronov from Vertex pharmaceuticals proposed a general ‘rule of thumb’ termed the 2-0 rule for kinase likeness to discriminating kinase inhibitors from the nonkinase molecules.

For kinase activity, the molecule should have

1) One or more heteroaromatic nitrogen’s,

2) One or more heteroaromatic NH group,

3) It contains one or more aniline, and 

4) It contains one or more nitriles.

Around 78% of the kinase compound passes the 2-0 rule.

Are Protein Kinases Drug Targets?

Kinases catalyze the transfer of phosphate groups from phosphate-donating molecules (like ATP) to other molecules. They have been intensively investigated as drug targets for many years. Around 20-25% of the druggable genome consists of kinases, and this target accounts for 20-30% of many companies' drug discovery programs.

Several protein kinase inhibitors have been approved by FDA and available in the market which includes Tykerb®, Sprycel®, Sutent®, Nexavar®, Tarceva®, Iressa®, and Gleevec®. Many other kinase inhibitors are currently undergoing clinical development. This accelerated the research and development in this area, reflecting the number of search results for 'kinase inhibitors'. Sci-finder keyword search resulted in 1281 patents, which is filed in 2007 alone. Drug and Market Development’s (D&MD) report (2005) shows that kinase targeted therapies growing from $12.7 billion in 2005 to $58.6 billion in 2010. 

 

So what is the problem with kinases? The lack of selectivity for targeting a specific kinase is the issue due to the similarity of other kinase targets. For example, the natural product substrate Staurosporine hits almost every kinase out there will be gratuitously toxic. However, the real problem with kinase inhibitors is the toxic outcomes may result from tissue distribution of orally administered kinase inhibitors.

 

Kinases are drug targets. But, difficult ones.

Phosphonium Coupling

A recent review article,Eur. J. Org. Chem. 2009, 461-479 by Kang F. et al., describes a new, efficient, chemoselective and versatile phosphonium mediated tautomerization-activation methodology for tautomerizable heterocycles.

Phosphonium Coupling affords the direct C-N, C-S, C-O and C-C bond formation of electron deficient heterocycles with various nucleophiles (with boronic acid for C-C) via C-OH bond activation using phosphonium salts.
The author believes that the reactivity of the C-OP+ is similar to that of C-Br, so that direct bond formation can be achieved via either SNAr displacement or transition metal catalyzed cross coupling under mild condition.


This Phosphonium Coupling leads to the most efficient synthesis of biologically important nucleosides from unactivated, unprotected, commercially available starting materials.

N-Methylation and Oral Bioavailability.

Inspired by the excellent pharmacokinetic profile of transplantation drug, cyclosporine A (a natural, N-methylated cyclic peptide), which can be administered orally, Kessler reported that multiple N-methylation is a promising way to rationally improve key pharmacokinetic characteristics in peptides.

N-methyl scan of the cyclopeptidic somatostatin analog cyclo(-PFwKTF-), known as the Veber−Hirschmann peptide, improves not only oral bioavailability but also receptor selectivity.

Another interesting question is to what extent might the N methylation contribute to the bioavailability (the ADMET profile) in the amide of small molecules rather than peptides? For example, Tubulin-binding taxanes such as paclitaxel and docetaxel are important cancer chemotherapeutic agents. However, these drugs suffer from limitations such as poor aqueous solubility and oral bioavailability, emerging drug resistance, and the lack of blood-brain barrier permeability.

N-methyltaxol C (methylation of the C3′ amide of taxol C), a potential impurity in clinically used taxanes, showed improved bioavailability. This result demonstrates the utility of N-methylation to improve key pharmacokinetic characteristics in amides.

The making of hERG free molecules (The Role of Fluorine)

The unwanted hERG affinity could be removed by moderating 

1) basicity (control pka),

2) lipophilicity of the compound, and 

3) steric environment of the central nitrogen 

A paper in BMCL from Pfizer reported the pka, lipophilicity, independent optimization of hERG affinity for the CCR5 antagonist ‘Maraviroc’. The steric demand and the dipole generated by the difluoro moiety of 4 4’difluoro cyclohexyl group in maraviroc are clearly not tolerated within the hERG channel.

 

Overcoming hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achieved by making axial fluorine in the piperidine ring.