• Background knowledge

  Under hypoxic conditions, the expression of HIF-1α increases, which leads to cancer malignancy, such as increased proliferation and metastasis of cancer cells, promotion of angiogenesis, and activation of cancer metabolism.

• Target diseases

  Lung cancer, liver cancer, blood cancer, colon cancer, pancreatic cancer, etc.

• OCG-01-0713

  Anticancer efficacy shows up due to the degradation of intracellular HIF-1α protein, which is promoted by suppression of the respiratory electron transport in mitochondria. (Exp. Mol. Med. 52, 2020)

• Current situation

  Optimization

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  (A) Suppression of mitochondrial respiration

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  (B) Increase of intracellular oxygen level in the presence of OCG-01-1564

• 

  Exp. Mol. Med. 52 (2020) 1845.

The microenvironment of solid tumor tissue is hypoxic, deprived of oxygen. Hypoxia-inducible factor-1 (HIF-1) accumulates under hypoxia and is degraded under normoxia. HIF-1α forms a complex with HIF-1β in the nucleus to increase the expression of various proteins involved in cancer malignancy, including rapid proliferation, metastasis, angiogenesis, activation of cancer metabolism, suppression of apoptosis, immunity to activating agents, and drug resistance. Especially, HIF-1α increases the expression of genes involved in the metabolic adaptation of cancer cells, such as aerobic glycolysis, glutaminolytic flux and amino acid and lipid metabolism. Thus, HIF-1α is considered as a potential therapeutic target. Gregg Semenza, Peter Ratcliffe, and William Kaelin, who studied the HIF-1α protein, were awarded the 2019 Nobel Prize in Physiology and Medicine. For the first time, the HIF-2α inhibitor Welireg (Belzutifan, Merck Co. Ltd.) targeting kidney cancer was approved by FDA in 2021.

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  Trends in Molecular Medicine 25 (2019), 33

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  Cell Death Dis. 8 (2017), e2843