Abstract

With multiple academic drug discovery centers in the US and around the world developing compounds for AD and other CNS indications, there is an opportunity to pull together a library of optimized compounds from a wide variety of programs. Here, we propose a simple program whereby screening and early stage drug discovery groups with a significant interest in neurodegenerative, psychiatric and other CNS disorders, deposit into a central repository compounds that have shown significant CNS‐relevant activity. These compounds would not simply be the hits from primary screens but rather would be fraction of compounds that have gone on to show activity in secondary assays, have benefited from medicinal chemistry optimization, or are otherwise characterized and promising as potential leads. This relatively small but highly selective library of active and relevant compounds will then be made available to academic drug discovery centers with the intention that they each include the shared library in their ongoing screening. This will increase the exposure of the shared library compounds to a wide range of assays, possibly identifying novel activities for the compounds. The proposed program includes several steps to simplify the exchange of compounds without the need for lengthy agreements or licensing arrangements. This initiative is intended as a low cost and administratively simple way to maximize drug discovery efforts within the neuroscience community. Whereas the program is initially envisioned as an academic collaboration, if successful it can be scaled to include biotech and other interested parties

1. Background and Significance

An increasing number of academic screening centers are devising a variety of high and medium throughput primary assays aimed at screening compound libraries with the intention of identifying structures that may warrant further development. Regardless of the particular target or screening approach adopted by any of the centers, we all would like to enrich our compound libraries with drug‐like compounds relevant to our targets, thus increasing the likelihood of valuable hits.

Here, we propose a simple program whereby screening centers with a significant interest in neurological, psychiatric and other CNS disorders exchange compounds that have shown some CNS‐relevant activity. By pooling these very selective and relatively small compound collections, we hope to both enrich each other’s libraries and to increase the exposure of our most interesting compounds to a wide variety of CNS‐relevant screens.

Ideally, this proposed shared library, the Collaborative CNS Screening Initiative (CCSI) library, should be highly enriched for optimized compounds and small enough to be readily added to ongoing screens at very little additional cost or effort. As such, only compounds that have distinguished themselves beyond primary screens should be included. These may include compounds that have emerged from secondary validation assays or medicinal chemistry programs, have particularly attractive drug‐like structures, or are otherwise noteworthy. The program is designed with a very low barrier for participation, avoiding protracted inter‐institutional agreements and other administrative hurdles.

This program is intended as a low cost, administratively simple, non‐competitive mechanism for maximizing the effectiveness of our individual drug discovery efforts. The CCSI library is not intended to replace existing, larger libraries. The program is not intended to compete with or replace more established, shared screening programs. This novel program would benefit drug discovery efforts for Alzheimer’s disease and aging deficits as well as broader CNS diseases.

2. Specific Aims

  • Define specific parameters for including compounds in the Collaborative CNS Screening Initiative (CCSI) library
  • Invite relevant CNS drug discovery centers to submit their most interesting compounds. Compounds will be coded but submitted anonymously, without structures
  • Assemble (onto 384‐well plates) these relatively small collections into a single CCSI library, and create a database to hold source compound information, for tracking purposes
  • Dispatch the full CCSI library to each participating center with the intention that the CCSI library is included in all future, relevant screens run by each center
  • When a novel activity is identified by a screening group, connect the center that contributed the compound of interest to the center that discovered the novel activity, and leave it to those parties to discuss further development of the compound
  • Publicize the program via email, web and conferences, with the intention of growing the number of groups contributing to and using the CCSI library