Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Abstract

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery.

Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

“…It is probably due to lack of representation of the chemical space by the those inhibitors, or variations in detection methodologies to access hERG blockade. Development of in silico models may be benefited from the data of a large collection of diverse compounds generated by electrophysiology.In 2005, NIH launched the decade-long of Molecular Libraries Program (MLPCN), offering the NIH-funded screen centers access to the large-scale screening capacity to identify small molecules that can be optimized as chemical probes by screening the molecular library small molecular repository (MLSMR) [19] . Based on the search in PubChem website (http://pubchem.ncbi.nlm.nih.gov), so far 553 primary screens for 486 protein targets have been completed, and the tested compound numbers varied from a few hundred up to approximately 300 000 compounds from the MLSMR compound collection.…”

The resurgence of phenotypic screening in drug discovery and development

“…[9] Perhaps surprisingly, detailed knowledge about smallmolecule MoA is not strictly required for FDA approval; of the 28 NMEs discovered between 1999 and 2008 by phenotypic approaches, nine of them still had unknown MoA. [2] In this regard, the standards required for claiming that a small molecule is a suitable chemical probe [10] are actually more stringent than those required for drug development. Although it has been proposed that almost 20% of drugs have an unclear MoA, cheminformatic approaches, such as similarity ensemble approach (SEA), suggest that targets may be inferred, and that the number may be closer to 4-5%.…”

Academia–pharma partnerships for novel drug discovery: essential or nice to have?

“…The funding model under which these sites operate varies widely. The National Institutes of Health Molecular Libraries Program was instrumental in building state-of-the-art screening and chemistry centers that supported more than a 1000 early drug discovery programs and yielded hundreds of useful chemical probes some of which progressed to drug development in collaboration with private industry [6]. This program operated within the academic environment, but its success relied on building successful collaboration with multiple stakeholders.…”