MK-3795

Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF-2α in MuSC, inducing Rb1 RNA expression, and repressing E2F-dependent proliferation. Transient HIF-2α inhibition rescues MuSC proliferation and muscle repair under iron-deficient conditions, highlighting HIF-2α as a potential therapeutic target to counteract sarcopenia in aging and chronic diseases.

Moreover, the combination of H2, silncARSR and PT2385 exerts significantly potentiated efficacy in modulating apoptosis-related protein expression and ultimately enhancing cancer cell mitochondrial apoptosis. The demonstrated high therapeutic efficacy and great biocompatibility of this Hydrogen-PT2385-silncARSR nanocomplex underscore the clinical translation potential for overcoming ccRCC sunitinib resistance.

Renal surgery after or during exposure to a HIF-2α antagonist is safe and feasible, with rates of both transfusions and complications commensurate with the reported literature from standard renal surgery. GRs of index renal tumors that eventually needed surgical intervention did not show a significant difference before, during, and after therapy. Tumors exhibiting a positive GR on drug may represent the indication that drives early surgical intervention prior to the tumor reaching the 3 cm threshold. A median washout time of 10 days from last dose of HIF-2α antagonist to surgery was safe and well tolerated.

In addressing the treatment of pVHL-deficient tumors, hypoxia-inducible factor 2α (HIF-2α) has risen as a promising therapeutic target, culminating in the development of specific inhibitors like PT2385 and its analogues...Additionally, the safety profile of PMMF showed minimal systemic post-treatment cytotoxicity. In summary, our findings position PMMF as a promising platform for treating tumors with pVHL deficiency and underscore the therapeutic potential of metalloimmunotherapy.

Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model...Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness.

This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols.

Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.

P1, N=110, Active, not recruiting, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2024 --> Nov 2026

Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

P1, N=110, Active, not recruiting, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2023 --> Nov 2024

P2, N=4, Completed, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Active, not recruiting --> Completed | Trial primary completion date: Nov 2023 --> Aug 2023

PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.