Target 2035: probing the human proteome

Carter, Adrian J.; Kraemer, Oliver; Zwick, Matthias; Mueller‐Fahrnow, Anke; Arrowsmith, C.H.; Edwards, A.M.

doi:10.1016/j.drudis.2019.06.020

Cited by 152 publications

(135 citation statements)

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“…We find that a significant portion of well-known druggable target classes remain underexplored, and that other druggable protein families, some large and with strong disease association, are almost entirely orphan of inhibitors. The list of 3440 proteins from 46 druggable target classes compiled here may help strategize emerging efforts to systematically develop chemical reagents for the human proteome (Carter et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Born from both this favorable context and also the realization that chemical probes can play a decisive role in the discovery of novel therapeutic targets (Arrowsmith et al, 2015; Oprea et al, 2018), large-scale efforts are ongoing to increase the chemical coverage of specific protein families, such as protein kinases, solute carriers, GPCRs and epigenetic target classes (César-Razquin et al, 2015; Knapp et al, 2012; Roth et al, 2017; Scheer et al, 2019; Wu et al, 2019). Based on the progress with these efforts, a vision is emerging to create chemical ligands for the entire druggable genome by year 2035 (Carter et al, 2019). Delineating what is the druggable genome will help guide this ambitious enterprise (Finan et al, 2017; Hopkins and Groom, 2002; Nguyen et al, 2017; Oprea et al, 2018; Russ and Lampel, 2005; Santos et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Of these, 46 are populated with 20 or more proteins, and could be the object of a focused medicinal chemistry effort where knowledge acquired and ligands discovered for one protein may guide and accelerate the design of ligands for another, as was done for kinases (Elkins et al, 2016) or bromodomains (Wu et al, 2019). We believe that these 46 protein families (Table 2) representing 3440 proteins (Supplementary Table 3) could be a good place to start a global effort towards the discovery of chemical ligands for the druggable proteome (Carter et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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The Druggable Genome as Seen from the Protein Data Bank

Wang

Yazdani

Han

et al. 2020

Preprint

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Almost twenty years after the human genome was sequenced, the wealth of data produced by the international human genome project has not translated into a significantly improved drug discovery enterprise. This is in part because small molecule modulators that could be used to explore the cellular function of their target proteins and to discover new therapeutic opportunities are only available for a limited portion of the human proteome. International efforts are underway to develop such chemical tools for a few, specific protein families, and a “Target 2035” call to enable, expand and federate these efforts towards a comprehensive chemical coverage of the druggable genome was recently announced. But what is the druggable genome? Here, we systematically review structures of human proteins bound to drug-like ligands available from the protein databank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. We show that the vast majority of druggable protein families, including some highly populated and deeply associated with cancer according to genomic screens, are almost orphan of small molecule ligands, and propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chemical probe discovery efforts.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Druggable Genome as Seen from the Protein Data Bank

Wang

Yazdani

Han

et al. 2020

Preprint

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“…These KCGS compounds can also be used as starting points for development of high-quality chemical probes as the biological function of their kinase targets becomes better understood and the investment in additional optimization is warranted. We utilized a recent data set [23,24] annotated to human protein-coding genes and their genetic relevance to look at the frequency of PubMed publications on individual kinases. Fig 1 depicts the publication counts for kinases covered by KCGS.…”

Section: Kinase Coveragementioning

confidence: 99%

“…Future expansion of KCGS will focus on filling the gaps in coverage of the dark kinases. (Table S2) [23,24]…”

Section: Kinase Coveragementioning

confidence: 99%

The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification

Wells

Al-Ali

Andrews

et al. 2019

Preprint

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We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.

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