Fig 1.
Schematic: Utilization of the KCGS.
(a) Disease relevant phenotypic screen highlights active compounds (b) Because all the targets are annotated, active molecules points to potential targets of interest. (c) Follow up experiments can be used to help confirm importance of these highlighted targets (d) Body of evidence implicates kinases that can be inhibited to impact disease.
Fig 2.
The screenable protein kinome.
Using assays from 10 vendors a total of 436 unique non-mutant human protein kinases can be readily screened. (a) Subfamily representation of the protein kinases that were not available through the 10 vendors. Nearly half of the unscreenable human kinome is composed of pseudokinases (b) Histogram illustrating how many vendors can be used to screen across the kinome. For example, there are 43 kinases that all 10 vendors have screens for (“all” bar). There are another 109 kinases screened by 9 out of 10 vendors (“9/10” bar). There are 38 kinases that only 1 out of the 10 vendors has assays for (“1/10” bar). Note: Our definition of the “screenable kinome” is those kinases for which there is a commercial assay that can be accessed. It is likely that assays could indeed be configured for many of the kinases not currently on this list.
Fig 3.
Selectivity profile of PKIS2 compounds using DiscoverX KINOMEscan.
Selectivity Index analysis of PKIS2. 357 compounds demonstrate an SI(65) of <0.04 at 1 μM, and thus inhibit less than 4% of the kinases in this screening panel with more than 65% inhibition at the 1 μM screening concentration.
Fig 4.
Examples of compounds for the KCGS from (a) PKIS, (b) PKIS2, and (c) the literature that are suitable (narrow) or not suitable (broad) for inclusion in the KCGS.
Fig 5.
Representation of the kinome coverage of the virtual set of 457 narrow spectrum inhibitors.
Red background shows the human protein kinases ranked by number of citations. Blue bars show the protein kinases for which an assay is available at one of 10 commercial vendors. Black bars identify protein kinases that are covered by the virtual set of inhibitors (subset of PKIS, PKIS2, and literature) described in the text.
Fig 6.
Process map for construction of a public comprehensive protein kinase chemogenomic set (KCGS).