Target 2035 - update on the quest for a probe for every protein

Abstract

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

Fig. 1. Conceptual framework and strategic priorities for Target 2035. (A) Target 2035 integrates principles of open science, collaboration, and data sharing between scientists from academic, non-profit and industrial institutions. (B) Target 2035 will be executed in two phases (phase I and II), with clearly defined strategic priorities aligned with the ultimate goal to develop chemogenomic libraries, pharmacological and biochemical tool compounds (chemical probes), and/or functional antibodies for nearly all human proteins by the year 2035.

Fig. 2. Relationship between chemical compounds and their targets for chemical probes versus chemogenomic compound sets. Chemical probes (CP)s are small molecules that are potent, selective and cell-active. Ideally, a chemical probe negative control is identified and used in parallel in phenotypic assays. A chemical probe ideally binds to a single target but can also be useful if it targets just a small number (∼2–3) of very closely sequence-related proteins. A chemogenomics library (CGL) comprises chemogenomic (CG) compounds of different chemotypes for each target; the chemotypes have complementary selectivity profiles, and preferably distinct modes of action (such as orthosteric or allosteric modulation). In the schematic, a CGL was screened against targets A–J yielding phenotypic data for 8 targets. These data are interpreted in the context of the magnitude of the phenotypic response, the mode of action (colour of arrow) and the CG chemical structures and accompanying characterisation.