# Statistical and Clustering Analysis of Safety Profiles of FDA-Approved Protein Kinase Inhibitors
## 3 Results
### Cluster Analysis of the Spectrum of AEs for the Approved Protein Kinase Inhibitors
Figure 4: Heat map based on the Manhattan distance metric of each drug–drug pair safety profile. Analysis of the target proteins of each drug revealed distinct distribution patterns, as presented in Table 6. Cluster 6 is not displayed because it contains only one inhibitor, which is not associated with a target in PDKIB. \begin{table}
\begin{tabular}{c c c c c c c c c} \hline \hline \multirow{2}{*}{**Target**} & \multirow{2}{*}{**Class**} & \multicolumn{6}{c}{**Cluster Number**} \\ \cline{3-10}  & & **1** & **2** & **3** & **4** & **5** \\ \hline \multicolumn{10}{c}{AXL (AXL receptor tyrosine kinase)} \\ \hline NTRK2 (Neurottrophic receptor tyrosine kinase 2) & & & & & & & \\ \hline NTRK3 (Neurottrophic receptor tyrosine kinase 3) & & RTK & 100 & 0 & 0 & 0 & 0 \\ \hline ROS1 (ROS proto-oncogene 1) & & & & & & & \\ \hline ALK (Anaplastic lymphoma kinase) & RTK & 57.14 & 14.29 & 0 & 14.29 & 14.29 \\ \hline NTRK1 (Neurottrophic receptor tyrosine kinase 1) & RTK & 50.00 & 50.00 & 0 & 0 & 0 \\ \hline EGFR (Epidermal growth factor receptor) & RTK & 44.44 & 33.33 & 11.11 & 11.11 & 0 \\ \hline DDR1 (Discoidin domain receptor tyrosine kinase 1) & & & & & & \\ \hline DDR2 (Discoidin domain receptor tyrosine kinase 2) & & & & & & \\ \hline EPHA2 (EPH receptor A2) & & & & & & \\ \hline ERB4 (Erb-B2 receptor tyrosine kinase 4) & & RTK & 0 & 100 & 0 & 0 & 0 \\ \hline FGFR4 (Fibroblast growth factor receptor 4) & & & & & & & \\ \hline TEK (TEK receptor tyrosine kinase) & & & & & & & \\ \hline RET (Ret proto-oncogene) & RTK & 0 & 83.33 & 0 & 16.67 & 0 \\ \hline KIT (tyrosine-protein kinase KIT, CD117) & RTK & 10.00 & 80.00 & 0 & 10.00 & 0 \\ \hline PDFORA (Platelet-derived growth factor receptor alpha) & & RTK & 0 & 80.00 & 0 & 20.00 & 0 \\ PDGFRB (Platelet-derived growth factor receptor beta) & & & & & & & \\ \hline CSF1R (Colony-stimulating factor 1 receptor) & RTK & 33.33 & 66.67 & 0 & 0 & 0 \\ \hline FLT1 (Fms-related receptor tyrosine kinase 1, VEGFR) & & & & & & & \\ \hline FLT4 (Fms-related receptor tyrosine kinase 4, VEGFR) & & & & & & & \\ \hline FGFR2 (Fibroblast growth factor receptor 2) & RTK & 0 & 60.00 & 0 & 20.00 & 20.00 \\ \hline FGFR2 (Fibroblast growth factor receptor 2) & RTK & 0 & 60.00 & 0 & 20.00 & 20.00 \\ \hline KDR (Kinase insert domain receptor, VEGFR) & & & & & & & \\ \hline FLT3 (Fms-related receptor tyrosine kinase 3) & RTK & 0 & 57.14 & 0 & 28.57 & 14.29 \\ \hline \hline \end{tabular}
\end{table} 
Table 6: The targets of the analyzed protein kinase inhibitors and the percental distribution of their ligands in obtained clusters. \begin{table}
\begin{tabular}{c c c c c c c c c c} \hline \hline \multirow{2}{*}{**Advense Event (AE)**} & **Cluster 1 vs.** & **Cluster 1 vs.** & **Cluster 1 vs.** & **Cluster 2 vs.** & **Cluster 2 vs.** & **Cluster 2 vs.** & **Cluster 3 vs.** & **Cluster 3 vs.** & **Cluster 4 vs.** \\  & **Cluster 2** & **Cluster 3** & **Cluster 4** & **Cluster 5** & **Cluster 3** & **Cluster 4** & **Cluster 5** & **Cluster 4** & **Cluster 5** & **Cluster 5** \\ \hline death & no sig. & no sig. & no sig. & no sig. & no sig. & no sig. & no sig. & no sig. & no sig. & no sig. \\ diarrhea & (\(p-0.001\)) & no sig. & (\(p-0.001\)) & no sig. & no sig. & no sig. & no sig. & no sig. & (\(p-0.025\)) & no sig. \\ fatigue & (\(p-0.001\)) & no sig. & (\(p-0.010\)) & no sig. & no sig. & \(\gamma-3.26\) & no sig. & no sig  
Most compounds targeting receptor tyrosine kinases (RTKs) were predominantly found in Cluster 1 or Cluster 2, with a preference for Cluster 2. Conversely, inhibitors targeting non-receptor tyrosine kinases (NRTKs) exhibited clearer distribution patterns compared to the RTK class. Specifically, inhibitors of Janus kinases (JAK1, JAK3, TYK2), key players in cytokine receptor signaling [34], as well as [PERSON]'s tyrosine kinase and Spleen tyrosine kinase (important in B cell receptor signaling) [35], predominantly aligned with Cluster 1, reflecting similar AE profiles. JAK2 inhibitors also clustered predominantly in Cluster 1.