PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials

Abstract

The number of protein kinase inhibitors (PKIs) approved worldwide continues to grow steadily, with 39 drugs approved in the period between 2001 and January 2018. PKIs on the market have been the subject of many reviews, and structure-property relationships specific to this class of drugs have been inferred. However, the large number of PKIs under development is often overlooked. In this paper, we present PKIDB (Protein Kinase Inhibitor Database), a monthly-updated database gathering approved PKIs as well as PKIs currently in clinical trials. The database compiles currently 180 inhibitors ranging from phase 0 to 4 clinical trials along with annotations extracted from seven public resources. The distribution and property ranges of standard physicochemical properties are presented. They can be used as filters to better prioritize compound selection for future screening campaigns. Interestingly, more than one-third of the kinase inhibitors violate at least one Lipinski's rule. A Principal Component Analysis (PCA) reveals that Type-II inhibitors are mapped to a distinct chemical space as compared to orally administrated drugs as well as to other types of kinase inhibitors. Using a Principal Moment of Inertia (PMI) analysis, we show that PKIs under development tend to explore new shape territories as compared to approved PKIs. In order to facilitate the analysis of the protein space, the kinome tree has been annotated with all protein kinases being targeted by PKIs. Finally, we analyzed the pipeline of the pharmaceutical companies having PKIs on the market or still under development. We hope that this work will assist researchers in the kinase field in identifying and designing the next generation of kinase inhibitors for still untargeted kinases. The PKIDB database is freely accessible from a website at http://www.icoa.fr/pkidb and can be easily browsed through a user-friendly spreadsheet-like interface.

Keywords: approved drugs; chemometrics analysis; clinical trials; database; kinome; protein kinase inhibitors.

Figure 1

FDA-approved kinase inhibitors. Icotinib and baricitinib are approved by CFDA (China Food and Drug Administration) and by EMA (European Medicines Agency) respectively: (a) evolution of approved protein kinase inhibitors (2001–2017); (b) Structures of Type-I PKIs; (c) Structures of Type-I½ PKIs; (d) Structures of Type-II PKIs; (e) Structures of Type-I covalent inhibitors (ibrutinib, afatinib, osimertinib, neratinib, acalabrutinib), Type-III inhibitors (trametinib and cobimetinib) and PI3K lipid kinase inhibitor (idelalisib).

Figure 1

FDA-approved kinase inhibitors. Icotinib and baricitinib are approved by CFDA (China Food and Drug Administration) and by EMA (European Medicines Agency) respectively: (a) evolution of approved protein kinase inhibitors (2001–2017); (b) Structures of Type-I PKIs; (c) Structures of Type-I½ PKIs; (d) Structures of Type-II PKIs; (e) Structures of Type-I covalent inhibitors (ibrutinib, afatinib, osimertinib, neratinib, acalabrutinib), Type-III inhibitors (trametinib and cobimetinib) and PI3K lipid kinase inhibitor (idelalisib).

Figure 2

Representation of the different binding pockets targeted by kinase inhibitors. Blue, adenine binding site; green, hydrophobic pocket; red, allosteric pocket; and grey, adjacent allosteric pocket. The backbone of VEGFR2 (PDB ID 4ASD) is colored according to the following colors: yellow, hinge region; cyan, DFG motif; green, P-loop; purple, αC-helix; red, catalytic subunit; and orange, VAIK catalytic motif.

Figure 3

Overview of the PKIDB interface: Available data for each inhibitor are summarized over twenty-one columns. Filters above each column are provided to facilitate data visualization. Advanced searches can be performed by using operators and expression. Numerical <, ≤, >, ≥, =; String match =, *, !, {, }; Logical operator || (OR), && (AND). After filtering, the number of the remaining inhibitors is displayed in the top left corner. All fields of the table are sortable (alphabetically, numerically or both) by clicking on the column header (◆). In the first column, image upscaling is triggered by mouse hover.

Figure 4

Distribution of physicochemical properties of PKIs: (a) Number of hydrogen bond acceptors (HBA); (b) Number of hydrogen bond donors (HBD); (c) Number of rotatable bonds (NRB); (d) Number of heavy atoms (NHA); (e) Molecular weight (MW); (f) ClogP (RDKit); (g) Topological polar surface area (TPSA); (h) ClogP (ChemAxon). Pink areas represent values outside two standard deviations from the mean (95.4% confidence interval).

Figure 5

(a) PCA of FDA orally approved drugs and PKIDB containing 180 PKIs. Blue and red ellipses encompass 95% of the individuals from class “Oral drugs” and “Kinase inhibitors” respectively; (b) Corresponding correlation circle.

Figure 6

(a) PCA of PKIs colored by inhibitor type. Ellipses encompass 95% of individuals of each respective inhibitor type except for Type-III inhibitors because there were too few data points. “NaN” is also defined as “unknown kinase inhibitor Type”; (b) Corresponding correlation circle.

Figure 7

Principal Moments of Inertia (PMI) plot of orally approved drugs (in green) and PKIs (in yellow and red). Compounds a, b and c represent the extreme shape of the PKI dataset. Compounds d and e are the most spherical oral drugs.

Figure 8

Kinome tree exploring the protein kinase space. The maximum phase reached by an inhibitor is color-coded: phase 4 (red), phase 3 (orange) and phase 2 (green). The size encodes the number of PKIs per protein kinase: small size encodes a number of inhibitors less than 5, medium size encodes a number of inhibitors between 5 and 10 and large size encodes a number of inhibitors greater than 10.

Figure 9

Protein kinase inhibitors having reached the highest phase of clinical trials grouped by pharmaceutical companies.