Which aspects of HTS are empirically correlated with downstream success?
High-throughput screening (HTS) is a well-established hit-finding approach used in the pharmaceutical industry. In this article, recent experience at Novartis with respect to factors influencing the success of HTS campaigns is discussed. An inherent measure of HTS quality could be defined by the assay Z and Z' factors, the number of hits and their biological potencies; however, such measures of quality do not always correlate with the advancement of hits to the later stages of drug discovery. Also, for many target classes, such as kinases, it is easy to identify hits, but, as a result of selectivity, intellectual property and other issues, the projects do not result in lead declarations. In this article, HTS success is defined as the fraction of HTS campaigns that advance into the later stages of drug discovery, and the major influencing factors are examined. Interestingly, screening compounds in individual wells or in mixtures did not have a major impact on the HTS success and, equally interesting, there was no difference in the progression rates of biochemical and cell-based assays. Particular target types, assay technologies, structure-activity relationships and powder availability had a much greater impact on success as defined above. In addition, significant mutual dependencies can be observed - while one assay format works well with one target type, this situation might be completely reversed for a combination of the same readout technology with a different target type. The results and opinions presented here should be regarded as groundwork, and a plethora of factors that influence the fate of a project, such as biophysical measurements, chemical attractiveness of the hits, strategic reasons and safety pharmacology, are not covered here. Nonetheless, it is hoped that this information will be used industry-wide to improve success rates in terms of hits progressing into exploratory chemistry and beyond. The support that can be obtained from new in silico approaches to phase transitions are also described, along with the gaps they are designed to fill.
Bender
Andreas
A
Lead Finding Platform, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Bojanic
Dejan
D
Davies
John W
JW
Crisman
Thomas J
TJ
Mikhailov
Dmitri
D
Scheiber
Josef
J
Jenkins
Jeremy L
JL
Deng
Zhan
Z
Hill
W Adam G
WA
Popov
Maxim
M
Jacoby
Edgar
E
Glick
Meir
M
D000818:Animals; D001681:Biological Assay; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D011208:Powders; D015397:Program Evaluation; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*
D011208:Powders; D054852:Small Molecule Libraries