What innovative therapies are expected to bring to the Nobel Prize-winning "oxygen-aware pathways"?

Professors William GKaelin (left), Professor Peter JRatcliffe (centre), and Professor Gregg LSemenza (right) (pictured)Nobel Prize-winning scientific research is not only an important breakthrough in basic research, but also often fosters innovative treatments that change the treatment of diseasesFor example, last year's Nobel Prize-winning physiology or medicine laureate, Professor James Allison, and professor Ben Yu's study of immuno-checkpoints CTLA-4 and PD-1 not only directly led to the targeted CTLA-4 anticancer therapy Yervoy and the targeted PD-1 anticancer therapy Opdivo, but also led to the emergence of immunocheckpoint inhibitor therapy, revolutionizing the landscape of cancer treatmentWhat patients will this year's Nobel Prize-winning "oxygen-aware pathway" benefit? Today's Drug Mingconde Content team will explore innovative therapies that this signaling pathway bringsinnovative treatment for anemia
the core part of the oxygen-aware pathway is the HIF-1 protein, which activates several genes in animal cells that react to the hypoxic environment, including VEGF, erythropoietin, EPO, and moreThese gene-expression proteins stimulate the production of red blood cells, angiogenesis and other physiological processes, helping the body to get more oxygena map of the pathway sensing oxygen in organisms (Photo: Credit: Cassio Lynm)innovative therapies that target this pathway have shown excellent results in treating anemia patientsIn anemia patients, there are not enough red blood cells in their bodies to deliver enough oxygen to various parts of the bodyin treating anemia, Amgen's recombinant erythropoietin (EPO) is an effective treatment that has been around for 30 yearsEPO is also a downstream target of oxygen-aware pathways, regulated by hIF-1 proteinsIn recent years, several biopharmaceutical companies have developed innovative therapies to regulate the body's response to hypoxia by raising levels of HIF-1 proteinsBecause hIF-1 protein scans several physiological processes associated with the solution of hypoxia, including the production of red blood cells and the transportation of iron, the target HIF-1 protein regulator is expected to achieve better therapeutic results than EPO the mechanism of action of the hypox-inducing factor protalysine hydroxylase inhibitor (HIF-PHI) (Photo: Source: Reference s3) there are currently at least 6 low-oxygen-inducing factor protosconocoline hydroxylase inhibitors (HIF-PHI) in clinical development HIF hydroxylase is modified by HIF, resulting in HIF degradation by proteases, thereby reducing HIF levels in the body It is an important regulatory mechanism for reducing HIF levels in oxygen-rich environment HIF-PHI improves HIF-1 levels by inhibiting the effect of HIF protalysine hydroxylase, thus reducing anemia "first-in-class" HIF-PHIstastat, developed by Fibrogen, AstraZeneca and Astellas, was first approved in China in December to treat patients undergoing dialysis treatment for anemia caused by chronic kidney disease (CKD) Not only was it approved this year to extend the indications in China, treating patients with renal anemia that does not require dialysis treatment, but also was approved in Japan , Bayer's Molidustat and GlaxoSmithKline's daprodustat have also submitted applications for new drugs in Japan, while Akebia Therapeutics' vadadustat and Zydus Cadila's desiatdust are in phase 3 clinical development part of the HIF-PHI molecular structure (Photo: Meodipt (Public domain)) innovative treatment of cancer
in a variety of cancers, due to the rapid proliferation of cancer cells, usually causes a local oxygen supply near the tumor, so cancer cells often improve the expression of HIF-1 alpha protein, stimulate the body's blood vessels to grow, provide more oxygen and nutrients for the tumor In addition, mutations in different genes can also lead to increased expression of HIF-1 alpha, including functional acquired mutations of cancer-causing genes (e.g ERBB2), and functional loss of mutations in anti-cancer genes (e.g VHL and PTEN) HIF-1-regulated genes are closely related to tumor metabolism, proliferation, survival and metastasis, and tumor vascular hyperplasia Therefore, the inhibition of HIF-1 protein and its related protein (HIF-2 alpha) function has also become an important direction of anti-cancer drug development parts of cancer-related genes regulated by HIF-1 (Photo: Source: Supplied) however, there is currently no approved HIF inhibitor The main challenge in this direction of development is the discovery of specific HIF inhibitors Another reason that may reduce the effect of HIF inhibitors is that the functions of different members of the HIF protein family can complement each other For example, studies have shown that the expression of low HIF-1 alpha can lead to increased compensatory expression of HIF-2 alpha This means that to inhibit the growth of cancer, both HIF-1 alpha and HIF-2 alpha may need to be targeted Because of the important function of HIF signaling pathways in stimulating the growth of red blood cells, a common side effect of HIF inhibitors is anemia, which also affects their safety in treating cancer patients currently, anticancer therapies that specifically target HIF signaling pathways include the "first-in-class" HIF-2 alpha inhibitor PT2977 developed by Peleton Therapeutics It can specifically bind to HIF-2 alpha, inhibiting the binding of HIF-2 alpha to HIF-1 beta It is currently used in Phase 2 clinical trials to treat patients with advanced renal cell carcinoma associated with VHL MsSA bought Peleton for $2.2 billion in May another anti-cancer therapy that targets the HIF signaling pathway is Roche's antisense oligonucleotide therapy RO7070179, which targets HIF-1 alpha This antisense oligonucleotide therapy is currently treating patients with hepatocellular carcinoma in Phase 1b clinical trials The results showed that RO7070179 was able to reduce mRNA levels of HIF-1 alpha in patients with disease stabilization and partial lytome conclusion In addition to treating anemia and cancer, HIF-1 alpha stabilizers are also used to treat inflammatory bowel disease Academic studies suggest that HIF-2 alpha may also be a new target for the treatment of non-alcoholic fatty hepatitis transforming breakthrough scientific research into innovative treatments that change patients' lives is not easy It has been 15 years since Mr Thomas Neff, the founder of Uber, founded the company to Rosas The Nobel Prize-winning RNAi technology took 12 years from the nobel prize to the birth of the first RNAi therapy We look forward to the news that Oxygen-aware Pathways will win the Nobel Prize, which will facilitate the development of innovative therapies based on this pathway and provide patients with new treatment options at an early date this article: Photo by Adam Baker, 'Nobel Prize Medal in Chemistry' CC BY 4.0 (via Flickr References: , 1, The Nobel,, 2019, , 2016, , 2016 Albert Lasker Basic S Supplied S Essential S Essential S Discovery of Molidustat (BAY 85-3934): A Small-Oral Molecule HIF-Prolyl Hydroxylase (HIF-PH Pand) for the Treatment of Renal Anemia ChemMedChem, DOI: 10.1002/cmdc.201700783 Soni and Padwad, (2018) HIF-1 in cancer therapy: two decade long story of a transcription factor Actaica, Gossamer Bio Retrieved October 7, 2019, from Retrieved October 7, 2019, from Retrieved October 7, 2019, from Development of TargetingXia-Inducible Factor 1 and 2 for Cancer Therapy Yonsei Medical Journal, Doi: 10.3349/ymj.2017.58.3.489 Activation of the hypoxia-inducible factor 2 alpha hefyd es s to hepatic steatosis Nature Medicine, Merck to Acquire Peloton Therapeutics, Bolstering Oncology Pipeline Retrieved October 7, 2019, from s11 sgsk submits first regulatory application for daprodustat in Japan for patients renal anaemia to chronic kidney disease Retrieved October 7, 2019, from Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1 alpha in advanced an advanced hepatocellular carcinoma World J Clinical Oncology, doi: 10.5306/wjco.v10.i3.149