Molecular approaches to target discovery:--evaluating targets for anti-tuberculosis drug discovery programmes.

Selection of appropriate targets for launching antituberculosis drug discovery programmes is challenging. This challenge is magnified by the limited repertoire of 'validated targets' and the paucity of clinically successful drugs. However, continued understanding of the biology of the microbe and its interaction with the host has enabled detailed evaluation of several interesting pathways and novel targets. The value of a target that is suitable for antituberculosis drug discovery needs to be defined not only in the context of its 'essentiality' for survival in vitro but also against a variety of properties relevant to activities in the drug discovery process, e.g.; selectivity, vulnerability, suitability for structural studies, ability to monitor inhibition in whole cells etc. It is also rarely feasible to obtain all the relevant information on the target prior to the launch of a discovery programme. Thus, there is a continuous confidence-building exercise on the validity of a target. Several novel approaches have enabled exploitation of the mycobacterial genome and prioritisation of putative targets; the concept of 'sterilisation' is now being evaluated not only through the availability of structurally diverse probe compounds but also by the ability to characterise metabolic pathways in vivo. The impact of the current knowledge base on the different facets of 'target validation' relevant to antituberculosis drug discovery is discussed in this article with emphasis on developing appropriate matrix systems to prioritise them. The article also discusses the influence of lead generation approaches with specific reference to antibacterial drug discovery.

Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity.

The non-steroidal antiandrogens flutamide (Eulexin((R))), nilutamide (Anandron((R))) and bicalutamide (Casodex((R))) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5alpha-DHT has higher binding affinity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an affinity two to four times higher than 2-hydroxyflutamide, the active metabolite of flutamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhibits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than flutamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival benefits of flutamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival benefits, including those comparing flutamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone. In a direct comparative study, bicalutamide (50 mg, once daily) was compared with flutamide (250 mg, three times daily), each in combination with an LHRH-A. Both therapies were well tolerated, although more patients could not tolerate flutamide therapy: 25 flutamide plus LHRH-A and 2 bicalutamide plus LHRH-A patients withdrew from therapy due to diarrhoea. There were no statistically significant differences for time to progression or survival between the two antiandrogens. This clinical trial of bicalutamide confirms the prediction from preclinical studies that a 50 mg dose of bicalutamide would be appropriate for use in patients with advanced prostate cancer, and demonstrates that this bicalutamide dose is clinically effective when administered as part of CAB.