Current landscape and therapeutic prospects of indole hybrids for prostate cancer treatment: A mini-review

Abstract

Prostate cancer ranks second in incidence and fifth in mortality among all cancer types in males. This striking epidemiological profile highlights its status as a major health concern that poses a severe threat to men's lives and health globally. Although traditional chemotherapeutics and targeted therapies for prostate cancer have made considerable progress, critical challenges remain, including high metastatic potential, acquired drug resistance, and unfavorable prognosis in patients with advanced disease, highlighting the imperative to develop novel therapeutic strategies. Indole hybrids, versatile and promising anticancer scaffolds formed by integrating indole moieties with other pharmacophores, exhibit prominent multi-targeted regulatory capabilities in prostate cancer therapy, enabling simultaneous modulation of key oncogenic pathways to address the complex molecular mechanisms of both hormone-sensitive and castration-resistant subtypes. Compared to single-scaffold derivatives, indole hybrids demonstrate enhanced anticancer potency and reduced off-target toxicity via synergistic effects between conjugated moieties, while also showing potential in overcoming drug resistance by circumventing single-target mutation-induced resistance and inhibiting ABC transporters to reverse multidrug resistance. Moreover, their structural flexibility facilitates structural optimization for improved pharmacokinetic properties and tailored efficacy against specific prostate cancer phenotypes, making indole hybrids valuable candidates for developing novel therapeutic agents to meet unmet clinical needs in prostate cancer treatment. This review summarizes the recent advances in indole hybrids with anti-prostate cancer activity from 2021 to date, striving to open new directions for developing novel prostate cancer therapeutics.