TEAD inhibitors (Cedilla)

Hypoxia-inducible factor (HIF) is a central regulatory factor in detecting and adapting to cellular oxygen stress. Dysregulation of HIF is associated with various human diseases. Seven HIF modulators, including six prolyl hydroxylase (PHD) inhibitors and one HIF-2α inhibitor, have already been approved for the treatment of renal anemia and cancer, respectively.

This review summarizes HIF modulators patented in the 2021-2023 period. This review provides an overview of HIF downregulators, including HIF-1α inhibitors, HIF-2α inhibitors, and HIF-2α degraders, as well as HIF upregulators, including PHD, FIH, and VHL inhibitors, and HIF-2α and HIF-3α agonists.

Efforts should be made to address the adverse clinical effects associated with approved HIF-modulating drugs, including PHD inhibitors and HIF-2α inhibitors. Identification of the specific buried cavity in the HIF-2α and an opened pocket in HIF-3α offer an avenue for designing novel modulators for HIF-2α or HIF-3α. Given the similarities observed in the binding cavities of HIF-2α and HIF-3α, it should be considered whether the approved HIF-2α inhibitors also inhibit HIF-3α. A comprehensive understanding of the HIF signaling pathway biology would lead to the development of novel small-molecule HIF modulators as innovative therapeutic approaches for a wide range of human diseases.

Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required.Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.