natural products

Nature has been a source of medicines for millennia, with many drugs developed from plants and, since the discovery of penicillin, microbial sources (see more here and here). In the mid 1990’s, combinatorial biochemistry enabled the shift in Natural Products drug discovery from Nature to the laboratory bench.

Privileged Position of Natural Products in Drug Space

Most non-Natural Product drugs and drug-like leads explore underrepresented regions of biologically relevant chemical space, effectively missing opportunities to discover new targets as evidenced by the space covered by approved Natural Product drugs (Bauer et al). As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein–protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries can be developed based on underrepresented scaffolds and regions of chemical space associated with natural products.

Why Natural Products? Polypharmacology as a desirable goal

A number of reports (for example here and here) point to a revision of the single-target dominant paradigm in the drug discovery strategy in place since the mid 1990’s. Interestingly, the analysis by Swinney and Anthony of discovery strategies found that most first-in-class drugs were discovered by phenotypic screening. As pointed out recently by Douglas B. Kell, classical drug discovery started with an organism displaying a disease phenotype and involved the assay of various drugs to identify one or more that was efficacious. There was no need to discover (let alone start with) a postulated mechanism of drug action; for a successful drug, this could come later (often much later). This ‘function first’ approach (equivalent to ‘forward’ genetics), has led to the discovery of many drugs, most of them natural products, that are still in use (and mainly still without detailed knowledge of their mechanisms of action).

However, as a result of the genome sequencing programs, drug discovery changed to an approach that was based on the ability of chemicals to bind to or inhibit chosen molecular targets at low concentrations in vitro. This strategy needs follow-up tests of efficacy in whole organisms. This approach is thus ‘target-first’, and is equivalent to ‘reverse’ genetics, and (despite some spectacular new drugs that work on selected patients) has been rather ineffectual because the vast majority of small molecule drugs (90–95%) fail to go forward, even from the ‘first into humans’ phase, to become successful and marketable drugs; a set of phenomena known as ‘attrition’.

EntreChem focus on natural product analogs is a bet to go back to data-driven science, rather than hypothesis-driven research, in a quest to avoid attrition, especially the lack of efficacy of drugs in Phase II studies, and to explore the potential of multi-targeted drugs as compared to single-target combination approaches.

EntreChem strategy

EntreChem strategy for bringing Natural Products back in the forefront of Drug Discovery avoids the early stages of the classical Natural Products-based drug discovery programs (isolation of environmental samples, extract analysis, de-replication, lead identification) and starts with a known lead compound (either an approved, clinical-stage or bioactive molecule) over which we apply our technology to obtain new analogs difficult to obtain by other methods, effectively representing a barrier of entry to others (in addition to filed IP).

These new analogs are the source of better candidates for preclinical development, since the small-size, focused, libraries allow phenotypic screening including in vivo testing to prioritize low toxicity, high bioactivity analogs.

Additionally, since we obtain analogs of products with somewhat known properties, we are reducing risks, both technical and commercial, associated to previously unknown product families.