B14 - Repurposing Kinase Inhibitors for Non-Cancer Indications via Clinical Trial Mining

Introduction: : Traditional drug discovery is costly and time-intensive, often taking over a decade from target identification to approval. [1] Repurposing existing drugs with known safety profiles offers a faster, cost-effective alternative. [2] One highly druggable gene family is that of the protein kinases, consisting of enzymes that regulate key cellular processes such as growth, metabolism, and immune responses. Their importance in cellular function similarly implicates kinase signaling dysregulation in a wide range of diseases, including cancer, autoimmune disorders, and metabolic syndromes. [3] While kinase inhibitors have been developed primarily for oncologic applications, they are increasingly recognized for their potential in treating non-cancer conditions. [4] We sought to analyze clinical trial data from a network pharmacology perspective to identify the spectrum of diseases in which kinase inhibitors have potential application, highlight kinases linking multiple disorders, and reveal opportunities for further inhibitor repurposing.

Materials and

Methods: : Data from all clinical trials in stages 2-4 in which kinase inhibitors were used for treatment were downloaded from clinicaltrials.gov. Trials were filtered to remove studies conducted on cancer patients. Synonyms for conditions, drugs, and kinases were scraped and standardized to ensure consistent categorization. Data was cleaned, processed, and visualized using R, with networks constructed to map relationships between conditions (diseases), drugs, and kinases. Heatmaps of proteomically-characterized kinase inhibition profiles characterizing both on- and off-target kinase inhibition for each drug were also generated to identify drugs targeting kinases implicated in clinical trial data

Results, Conclusions, and Discussions:: Autoimmune and inflammatory disorders had the highest diversity of unique kinase inhibitors under investigation (Figure 1). Autoimmune and transplantation disorders were associated with the greatest number of clinical trials. Transplantation disorders exhibited relatively fewer unique inhibitors compared to autoimmune diseases. Network analysis showed multiple disease categories having shared kinase targets, with rheumatoid arthritis, COVID-19, and graft-versus-host disease associated with broad kinase inhibitor coverage (Figure 2). In contrast, conditions such as psoriasis and pulmonary fibrosis were associated with relatively few inhibitors. Kinases targeted in these diseases included tyrosine kinase 2 (TYK2) for psoriasis and rho-associated protein kinase 2 (ROCK2) for pulmonary fibrosis. Heatmap analysis identified strong TYK2 inhibitors as shown in Figure 3.

Network analysis reveals shared kinase targets across multiple condition categories, indicating significant potential for inhibitor repurposing. While autoimmune diseases show broad inhibitor diversity and trial activity, transplantation disorders had relatively fewer inhibitors, suggesting an underexplored area despite a high trial volume. Diseases such as psoriasis and pulmonary fibrosis, which have relatively few inhibitors tested in clinical trials but multiple kinase targets per heatmap analysis, represent promising opportunities for broader repurposing efforts for these disorders. Mapping inhibitors to kinase targets enables identification of mechanistically similar compounds that may be effective in related diseases. A limitation of this study is that not all trials reported the kinase targets of the inhibitors studied. To address this, future work will involve cross-referencing drug information with large-scale kinase profiling datasets, to infer kinase targets. Additionally, systematic literature analysis will be used to further map disease-kinase relationships.

Analyzing non-cancer clinical trial data reveals opportunities to repurpose kinase inhibitors for conditions often lacking treatment options such as transplantation disorders, psoriasis, and pulmonary fibrosis. Future efforts to expand target inference and literature integration will further improve the identification of new therapeutic opportunities for existing kinase inhibitors. Our analysis of non-cancer clinical trial data identifies promising opportunities to repurpose kinase inhibitors for conditions with limited treatment options, including transplantation disorders, psoriasis, and pulmonary fibrosis. Continued enhancement of target inference and data/literature integration methods has the potential to further accelerate the identification of novel therapeutic applications.

Acknowledgements and/or References (Optional):: [1] J. A. DiMasi, H. G. Grabowski, and R. W. Hansen, “Innovation in the pharmaceutical industry: New estimates of R&D costs,” Journal of Health Economics, vol. 47, pp. 20–33, May 2016.
[2] Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt HHHW. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 2022 Feb;43(2):136-150.
[3] L. K. Chico, L. J. Van Eldik, and D. M. Watterson, “Targeting protein kinases in central nervous system disorders,” Nat Rev Drug Discov, vol. 8, no. 11, pp. 892–909, Nov. 2009.
[4] Z. Xie, X. Yang, Y. Duan, J. Han, and C. Liao, “Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases,” J Med Chem, vol. 64, no. 3, pp. 1283–1345, Feb. 2021.