# Statistical and Clustering Analysis of Safety Profiles of FDA-Approved Protein Kinase Inhibitors
## 1 Introduction  
The human protein kinase gene family consists of over 538 members which regulate cell biology by modifying the functions of proteins through phosphorylation. Subsequently, phosphorylation enhances or reduces enzyme activity and alters other biological activities, such as transcription and translation [1]. Protein kinase inhibitors (PKIs) act by blocking the activity of these protein kinases, disrupting the cellular processes they regulate. They bind to the ATP-binding site of their target enzymes and extend into nearby hydrophobic pockets [2, 3]. Initially, PKIs were developed for cancer treatment. Over time, as new molecules emerged, their therapeutic indications expanded to include autoimmune diseases, inflammatory diseases, hypertension, and glaucoma. The clinical effectiveness of PKIs varies widely. For instance, imatinib has been highly effective against chronic myelogenous leukemia, while most other PKIs prolong survival in patients with cancer by only weeks or months beyond standard cytotoxic therapies [2, 4]. Despite the effectiveness of PKIs, the development of resistance is a common challenge, significantly limiting their long-term success [4]. Tumors and disease pathways often adaptto these treatments, through various resistance mechanisms such as mutations in the kinase target that prevent inhibitor binding, activation of alternative signaling pathways that bypass the blocked kinase, and upregulation of compensatory kinases that restore the disease-driving activity [5; 6; 7]. These adaptive responses not only reduce the therapeutic window but often lead to disease relapse and progression, forcing clinicians to explore alternative or combination therapies [8]. As a result, overcoming resistance and improving their therapeutic potential has become a primary focus in PKI research, pushing for innovative approaches. These include the development of next-generation protein- and oligonucleotide-based biologics targeting resistant mutations, the design of small-molecule inhibitors that target unique kinase conformational forms and binding sites, and combination therapies that simultaneously disrupt multiple pathways [4; 9]. Furthermore, the structural diversity and allosteric regulatory mechanisms of protein kinases offer new opportunities to discover small molecule inhibitors [10]. Since the approval of the first PKIs in the late 1990s and early 2000s, the field has grown exponentially, with nearly 100 approved therapeutics to date, 37 of which gained approval between 2016 and 2021 [11]. As of November 2022, 72 small molecule PKIs have been approved by the United States Food and Drug Administration (FDA). Among these, forty target receptor protein-tyrosine kinases, sixteen block nonreceptor protein-tyrosine kinases, and twelve inhibit protein-serine/ threonine protein kinases. Additionally, four drugs target cyclin-dependent kinase (CDK) 4 or 6 and dual specificity mitogen-activated protein kinase Via (MEK) 1/2, inhibiting the RAS-Raf-MEK-MAPkinase pathway. The most frequently targeted kinase family is the epidermal growth factor receptor (EGFR)/ErbB family, followed by the vascular endothelial growth factor receptor (VEGF), Janus kinase (JAK), fused breakpoint cluster region-Abelson murine leukemia viral oncogene homolog, Anaplastic Lymphoma Kinase, anaplastic lymphoma kinase, and fibroblast growth factor receptor (FGFR) families. Over two dozen of the approved drugs act as multi-kinase inhibitors [12]. Most of them are approved for the management of neoplasms. The therapeutic indications include solid tumors such as lung, colon, and breast, or nonsolid tumors such as leukemia, and some of them are used against both types of tumors. Several of them are approved for the treatment of non-neoplastic diseases in various therapeutic areas like eyecare, immunology, gastroenterology or dermatology. Some of them received approval for the treatment of more than one condition [12]. Therefore, the safety profile of the specific drug varies by target, indication and route of administration.