Researchers at Johns Hopkins University and the University of Maryland School of Pharmacy have developed a set of novel, first-in-class small molecule drugs that inhibit hypoxia-inducible factors 1 and 2 (HIF-1/2), a pair of transcription factors considered to be “master regulators” of cancer progression. Their study showed that these drugs can overcome resistance to immune checkpoint blockade therapy, and when combined with immunotherapy, can completely eliminate breast, colorectal, melanoma, and prostate tumors in mice, suggesting that they could eventually be used to treat a broad range of cancers in humans. Research lead Gregg L. Semenza, MD, PhD, a professor at Johns Hopkins University School of Medicine, is co-senior author of the team’s published paper in Journal of Experimental Medicine, titled “Targeting conserved domains of hypoxia-inducible factors for cancer therapy.” Hypoxia-inducible factors 1 and 2 are known as master regulators of cancer progression because they control the activity of hundreds of genes crucial for the survival, growth, and spread (metastasis) of cancer cells. HIF-1/2 levels rise in response to low oxygen levels (hypoxia), a condition commonly found in the center of rapidly growing tumors, the authors explained. “In response to hypoxia, cells in most metazoans activate a transcriptional pathway mediated by HIFs, which play a crucial role in adaptation to low O2 levels,” they wrote. “Many oncogene gain-of-function and tumor suppressor loss-of-function mutations increase HIF activity in an O2-independent manner.” Computer-aided drug design using the SILCS technology identified three sites on HIF-2 that are highly similar in HIF-1 and HIF-2 and…
