Aim: High-throughput phenotypic screens have emerged as a promising avenue for small-molecule drug discovery. The challenge faced in high-throughput phenotypic screens is target deconvolution once a small molecule hit is identified. Chemogenomics libraries have emerged as an important tool for meeting this challenge. Here, we investigate their target-specificity by deriving a 'polypharmacology index' for broad chemogenomics screening libraries.
Methods: All known targets of all the compounds in each library were plotted as a histogram and fitted to a Boltzmann distribution, whose linearized slope is indicative of the overall polypharmacology of the library.
Results & conclusion: Comparison of libraries clearly distinguished the most target-specific library, which might be assumed to be more useful for target deconvolution in a phenotypic screen.
The traditional 3 + 3 design continues to be commonly used for Phase I dose-finding oncology trials, despite increasing criticisms and development of innovative methods. Unfortunately, it is a challenge to convince principal investigators to use novel designs. The goal of this paper is to persuade researchers to break away from 3 + 3 design and provide potential solutions to better designs and implementation strategy. We reviewed the statistical methods for adaptive Phase I designs. The barriers among all the major components of the implementation team have been emphasized and potential solutions have been discussed. Institutional support to the principal investigators and statistician, as well as to other team members is essential to design and implement adaptive trials in academic medical institutions.
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