Current Landscape and Therapeutic Prospects of Indole Hybrids for Colorectal Cancer Treatment.

Colorectal cancer (CRC), a malignant tumor originating from the colon or rectum epithelium, is one of the most prevalent and lethal gastrointestinal cancers globally, with its pathogenesis closely linked to genetic mutations and dysregulated oncogenic pathways. Despite advances in traditional chemotherapeutics and targeted therapies, CRC still faces challenges such as high metastasis rates, drug resistance, and poor prognosis for advanced-stage patients, highlighting the need for novel therapeutic agents. Indole hybrids offer notable advantages in CRC therapy, as their structural flexibility enables the simultaneous targeting of multiple CRC-related oncogenic pathways and mutated proteins. Optimized modifications enhance target binding affinity, boost antiproliferative/pro-apoptotic activity, and improve pharmacokinetic profiles compared with traditional indole derivatives. Additionally, their multifunctional mechanism helps overcome drug resistance by bypassing cancer cell adaptive changes, and structural refinement reduces off-target toxicity. Accordingly, indole hybrids represent highly valuable molecular scaffolds for the discovery and development of novel therapeutic candidates against CRC. This review outlines the current landscape of indole hybrids with therapeutic potential against CRC, developed from 2021 to the present, aiming to open new avenues for the exploration of novel CRC therapeutic candidates.