The area has rightly acquired a reputation as a graveyard for drug hunters. With many big pharma research groups exiting the area over the last 15 years those remaining are to be applauded because undoubtedly the need for new, effective antibacterials remain high.
This seems to be an area prone more than most to the ‘latest idea’. Ten years ago genomics was going to allow us to identify all the essential targets and then prosecute them in a logical manner. The widespread failure of this “pile ‘em high/screen ‘em quick” approach (including the high-profile demise of the GSK group) has pushed many of the remaining companies back in the opposite direction towards screening natural product collections or libraries of dross DOS compounds. So it’s encouraging to find groups who have had the courage to retain their heads whilst all around were losing theirs. Whilst AZ senior management have not covered themselves with glory over the last few years, in this case their persistence is to be applauded.
What marks this publication ( http://pubs.acs.org/doi/abs/10.1021/cb300316n ) out is the successful progression of a novel anti-bacterial target from target identification, through to validating the target with lead molecules in an in vivo model. The authors suggest this is only the second time this has been done in the last 10 years.
Thymidylate kinase (TMK) is the enzyme that transfers phosphate from ATP to thymidine monophosphate to form thymidine diphosphate. It is essential for survival of cells because blockade stops DNA replication. TMK sits at the junction of the de novo and salvage metabolic pathways and has been explored as an antiviral and antimycobaterial target in the past. However, the difficulty of identifying good quality molecules has prevented TMK from being validated in vivo.
Unlike protein kinases, where the ATP molecule is buried in a lipophilic cleft, in TMK the ATP site is relatively solvent exposed meaning the most ‘druggable’ site is that which binds thymidine monophosphate. This also has the advantage of being the site that shows most difference when compared to the human orthologue and hence holds out the potential for achieving selectivity. Taking thymine as a starting point the authors made a series of heterocyclic analogues, attempting to mimic the sugar ring system with additional liphophilic substituents trying to pick up interactions with an identified hydrophobic pocket. TK-924 was their starting point for optimisation.
The authors describe an optimisation programme which made over 1000 compounds, each synthesised via a 10- to 15-step synthetic route-a truly Herculean effort! One wonders how many of the compounds were made at AZ and how many were made on contract (and perhaps sometimes the efforts of the CRO are never appropriately acknowledged!). Nevertheless optimisation led to TK-666. The synthesis is described in the supplementary material but for those of you who like to see such things here is the route-
The compound showed good enzyme activity against Gram positive bacteria, excellent selectivity vs. the human orthologue and good antibacterial activity (<1ug/ml) vs. pathogenic Gram-positive bacteria (including resistant strains). In the standard thigh model the compound showed efficacy at 100mg/kg by administration of a single intraperitoneal dose. Perhaps disappointingly the dosing route and activity point towards improvements that still need to be addressed by the medicinal chemistry programme.
Nevertheless an interesting new set of antibacterial compounds worthy of further exploration.