From Infection to Oncology: AI-Assisted Drug Repurposing Uncovers Anti-Infective and Excipient-Class Compounds as PPAR-α-Linked Anticancer Agents

Abstract

Drug repurposing offers an efficient strategy to identify novel anticancer agents from marketed compounds. We screened a library of ~1400 approved drugs using a PPARE–PPAR-α luciferase reporter assay to uncover modulators of lipid metabolism that induce cancer cell death without direct binding to PPARα. This primary screen identified 224 compounds inhibiting reporter activity by >50%, of which 26 demonstrated ≥50% cytotoxicity in KAIMRC1 breast cancer and HCT116 colorectal cancer cells at 10 µM after 48 h incubation. AI-based DrTarget analysis classified these hits, with Group 1 comprising four previously unrecognized anticancer agents: antibiotics cefditoren pivoxil, tebipenem pivoxil, broxyquinoline, and cosmetic ingredient 1-hexadecanol. Dose–response studies across KAIMRC1, HCT116, and SW480 cells revealed IC50 values as low as ~10 µM, comparable to daunorubicin, a well-known anti-cancer drug. Apoptosis profiling confirmed activation of intrinsic/extrinsic pathways via cytochrome c, SMAC/Diablo, TRAIL-R1/DR4, and phospho-p53 modulation. Based on these findings, we propose the repurposing of Broxyquinoline, 1-Hexadecanol, Cefditoren Pivoxil, and Tebipenem Pivoxil as potential anti-cancer drugs.