Hit Identification Strategies

The starting point of a medicinal chemistry program is the identification of an interesting hit. The definition of such a hit series varies and will be influenced by the TPP or TCP focus. Series potency is an important parameter (against wild-type and resistant strains) as such an EC50 of less than 1 pM is a typical cutoff so as to balance having sufficient numbers of 

---

Brough PA, Barril X, Borgognoni J et al (2009) Combining hit identification strategies fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52 4794—4809... 

Especially, after an initial HTS screen fails to produce viable hits, the pharmaceutical research seeks to expand its lead identification strategies. Therefore, NMR-based screening is gaining momentum relative to HTS-based techniques [65-68]. 

A detailed description of screening methods used in FBLG is beyond the scope of this chapter many FBLG reviews are available [34-39]. We will just briefly outline some of the assays used for fi agment hit identification before exploring strategies and tactics employed in hit optimization. 

Fig. 7.1. The strategy used to develop GGTI. A pilot library consisting of 171 compounds were screened for the ability to inhibit GGTase-I using RhoA as a substrate. This led to the identification of two groups of compounds, one with tetrahydropyridine scaffold and the other with dihydropyrrole scaffold. Solid-phase split-and-pool combinatorial synthesis of a large number of analogs of these initial hits led to the identification of P3-E5 and P5-H6. More than 700-fold increase in IC50 value for the inhibition of GGTase-I was obtained in the case of P3-E5 compared with the initial compound. Further derivatization of P5-H6 and P3-E5 led to cell active compounds P61-A6 and P61-E7, respectively.

---