Novel anticancer drug discovery strategies targeting hypoxia-inducible factors

Introduction: Hypoxia is a key feature of solid tumors, associated with aggressive behaviors such as radiation and chemotherapy resistance, increased metastasis, and poor prognosis. Hypoxia-inducible factors (HIFs) are essential transcription factors that help tumor cells adapt to hypoxic environments by promoting the expression of pro-oncogenic genes. Reducing HIF activity presents a promising strategy for advancing cancer treatment.

Area covered: In this paper, the authors present an overview of recent studies on the development of HIF-1/2 inhibitors as potential anticancer drugs. The article offers a comprehensive analysis of the structural characteristics of these inhibitors and explores their relationship with anticancer activity, focusing on research conducted over the past decade, from 2015 to 2024.

Expert opinion: Because they play a big role in medicinal chemistry and the discovery of anticancer drugs, HIF inhibitors have always gotten a lot of attention and have been used to make a lot of important molecules with different biological effects, especially in the field of cancer research. Several techniques and chemical scaffolds have successfully targeted HIF-1α. However, additional research is required to sustain HIF-1α inhibition while maintaining anticancer activity. The FDA approval of Belzutifan provided researchers with an opportunity to conduct broader HIF-2 studies.