Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds.[1][2] These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO).[3][4] The drug discovery process generally follows the following path that includes a hit to lead stage:
Target validation (TV) → Assay development → High-throughput screening (HTS) → Hit to lead (H2L) → Lead optimization (LO) → Preclinical development → Clinical development
The hit to lead stage starts with confirmation and evaluation of the initial screening hits and is followed by synthesis of analogs (hit expansion). Typically the initial screening hits display binding affinities for their biological target in the micromolar (10−6 molar concentration) range. Through limited H2L optimization, the affinities of the hits are often improved by several orders of magnitude to the nanomolar (10−9 M) range. The hits also undergo limited optimization to improve metabolic half life so that the compounds can be tested in animal models of disease and also to improve selectivity against other biological targets binding that may result in undesirable side effects.
On average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug.[5]
^Deprez-Poulain R, Deprez B (2004). "Facts, figures and trends in lead generation". Current Topics in Medicinal Chemistry. 4 (6): 569–80. doi:10.2174/1568026043451168. PMID 14965294.
^Fruber M, Narjes F, Steele J (2013). "Lead Generation". In Davis A, Ward SE (eds.). Handbook of Medicinal Chemistry: Principles and Practice. RSC Books. pp. 505–528. ISBN 978-1849736251.
^Keseru GM, Makara GM (Aug 2006). "Hit discovery and hit-to-lead approaches". Drug Discovery Today. 11 (15–16): 741–8. doi:10.1016/j.drudis.2006.06.016. PMID 16846802.
^Bleicher KH, Böhm HJ, Müller K, Alanine AI (May 2003). "Hit and lead generation: beyond high-throughput screening". Nature Reviews. Drug Discovery. 2 (5): 369–78. doi:10.1038/nrd1086. PMID 12750740. S2CID 4859609.
^Ezekiel J. Emanuel. "The Solution to Drug Prices". New York Times. On average, only one in every 5,000 compounds that drug companies discover and put through preclinical testing becomes an approved drug. Of the drugs started in clinical trials on humans, only 10 percent secure F.D.A. approval. ...
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