Discovery of Novel Potent Molecule for Treating Cisplatin-Induced Acute Kidney Injury Driven by Phenotypic Screening

Cisplatin-induced acute kidney injury (cis-AKI) is the primary organ toxicity that occurs during cisplatin-based Cancer treatment, and currently, there is a lack of effective treatment methods. The occurrence of cis-AKI involves complex pathophysiological processes, therefore, phenotypic screening-based drug discovery may be more applicable for identifying lead compounds to treat cis-AKI. In this study, a cascading phenotypic screening was designed and implemented. Through this protocol, a potent compound, CX116, was obtained, which exhibits potent anti-inflammatory activity and effectively protects cells from cisplatin toxicity. Mechanism studies indicated that CX116 exerts its effects by inhibiting the inflammatory response, reducing oxidative stress, protecting mitochondrial function, and counteracting Apoptosis. In vivo studies showed that CX116 bears acceptable toxicity and appropriate pharmacokinetic properties, and significantly protects renal tissue from cisplatin-induced damage in a cis-AKI animal model. In conclusion, CX116 is a highly promising active molecule and holds great potential for the development of therapeutic drugs for cis-AKI.