Recent Progress and Therapeutic Potential of Indole Hybrids Against Colorectal Cancer

Colorectal cancer (CRC) represents one of the most prevalent and lethal malignancies worldwide, with rapidly increasing global incidence and mortality. Current clinical therapies for CRC are severely compromised by tumor metastasis, intrinsic and acquired drug resistance, and unsatisfactory prognosis for advanced patients, highlighting an urgent demand for novel and effective therapeutic candidates. As privileged multifunctional scaffolds, indole hybrids integrate diverse pharmacophores to achieve simultaneous modulation of multiple CRC-associated oncogenic signaling pathways and mutant proteins, enabling them to overcome the limitations of traditional single-target drugs, reduce systemic toxicity, and optimize pharmacokinetic performance. This review comprehensively summarizes the research progress of novel indole hybrids for anti-CRC therapy reported since 2021, excluding indole-pyrimidine and indole-pyridine hybrids covered in previous studies. Notably, among all summarized subclasses, indole-chalcone/chromene, indole-hydroxamic acid/benzamide, and indole-azole hybrids, show the most prominent and promising therapeutic outcomes. These three dominant hybrid categories display potent antiproliferative activity against both drug-sensitive and drug-resistant CRC cell lines, exert robust in vivo tumor growth inhibition in xenograft models, and possess favorable safety profiles with low cytotoxicity to normal cells. We systematically elaborate their key structure-activity relationships, core anti-CRC molecular mechanisms, including cell cycle arrest, apoptosis induction, and targeted pathway regulation, as well as superior preclinical pharmacological characteristics. Furthermore, the current challenges and future research directions for indole hybrid-based anti-CRC drug development are discussed.