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• Summary of the downstream genes of HIF-2α involved in clear cell renal cell carcinoma. • The inhibition mechanism of HIF-2α allosteric inhibitors is described in detailed. • Two key residues affecting the activity of HIF-2α inhibitors were analyzed. • The development of two categories of HIF-2α allosteric inhibitors were reviewed. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2α (HIF-2α) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2α inhibitors to the promising potency of the HIF-2α inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2α has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2α in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2α allosteric inhibitors. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001 , a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002 , an analog of M1001 , shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2. Image 1 • A reliable HIF-2 agonist binding mode is proposed by molecular dynamic simulations. • Nine HIF-2 agonist analogs are synthesized and evaluated to verify the binding mode. • Compound 10 with improved activity and reduced cytotoxicity is obtained. [ABSTRACT FROM AUTHOR]

• The discovery of PHD as a significant target for treating renal anemia. • The research and development process of the first approved PHD inhibitor, roxadustat. • Summary of features, properties, and clinical trial design of roxadustat. • Summary of the potential clinical application of roxadustat and related mechanism. Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug. This review presents recent advances in potential clinical applications of the representative prolyl hydroxylase inhibitor roxadustat and summarizes the overall research and development process, from target discovery to marketing. [ABSTRACT FROM AUTHOR]