Hit to lead program

Laboratories.172 A high throughput screen led to the identification of two distinct chemical series that have since entered a hit to lead program. The compounds inhibited PIP5K with nanomolar potencies and were selective against a panel of protein kinases including PI3K. 

The phases of drug discovery are target finding, hit finding, hit to lead program or lead finding, lead optimization (sometimes pre-clinical candidate selection), and finally clinical candidate selection. 

More recently, the focus has moved from diversity in favor of combinatorial libraries designed to target specific receptors or enzymes (12). While these single-target-focused libraries remain a key component of many drug-discovery programs, and are useful in both hit to lead and lead optimization contexts,... 

A smaller (prima ) panel of targets is usually sufficient during the hit to lead phase and lead optimization phases of a drug discovery program to detect promiscuous scaffolds and... 

If a chemical hit (series) identified from screening has clear potential chemical liability that would limit the ability to develop the compound and related analogs then it is unlikely to be selected with high priority to move into the hit-to-lead phase. This is less of an issue for probe development, for example oral bioavailability is rarely a criteria for a chemical probe (even if desirable), similarly potential in vivo toxicity liabilities of a hit are not of concern for initiating a probe development program. While medicinal chemists and pharmacologists on a drug discovery or probe discovery team... 

Scientists at AstraZeneca shared their experiences with their historical compound collections, which prompted them into defining a number of selection criteria in order to filter out compounds of little value for the hit-to-lead process [27]. Subsequently, this led to a compound collection enhancement program. 

Building blocks that render unique physicochemical properties and metabolic stability to drug candidates play a key role in advancing lead generation, hit-to-lead, and lead optimization programs in the pharmaceutical industry. One such example is the 3-azabicyclo[3.1.0]-hex-2-yl moiety (Figure 11.3), derivatives of which have found applications in the synthesis of therapeutic targets. ... 

---