Belzutifan: A Narrative Drug Review

Abstract

Von Hippel-Lindau disease is an autosomal dominant disorder characterised by renal cell carcinomas, pancreatic neuroendocrine tumours, central nervous system hemangioblastomas, retinoblastomas, and tumours of the reproductive tract. This disease results from loss of function mutations in the tumour suppressor gene known as the Von Hippel-Lindau gene, located on chromosome 3. Loss of function mutation in the Von Hippel-Lindau gene results in the accumulation of a protein known as a hypoxia-inducible factor, which promotes cellular proliferation and angiogenesis, leading to cancer. Belzutifan inhibits the hypoxia-inducible factor by binding to the Per-ARNT -Sim-B binding pocket on the hypoxia-inducible factor -2α, inhibiting cellular proliferation and angiogenesis. In our thorough literature review, we identified 37 relevant articles. Belzutifan showed clinically meaningful response rates for both Von Hippel-Lindau disease-associated renal cell carcinomas and non-renal cell cancers. The pharmacokinetic profile of belzutifan was much better than its congener molecules due to the optimisation of its dihalide groups from germinal to vicinal. The pharmacodynamic effect of belzutifan was confirmed by its ability to decrease serum erythropoietin, which is a direct result of hypoxia-inducible factor- 2α inhibition. The significant side effects observed were anaemia, hypoxia, fatigue, hypertension, visual impairment and weight gain. Multiple clinical trials are currently underway to determine the role of beluztifan as part of combination regimens in treating Von Hippel-Lindau disease-associated malignancies.

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

“…It acts by selectively blocking the dimerisation of HIF-2α with HIF-1β. As expected, anaemia is among the adverse effects of these agents [151]. Another molecule was shown effective in a murine model of hepatic cell carcinoma [152].…”

“…Various strategies have been attempted to block the HIF pathway in cancer; many molecules were abandoned for excessive toxicity. Belzutifan has been approved by the FDA for treating renal cell carcinoma and other tumours in patients with von Hippel-Lindau syndrome [151]. It acts by selectively blocking the dimerisation of HIF-2α with HIF-1β.…”

A novel risk score model based on four angiogenesis long non-coding RNAs for prognosis evaluation of pancreatic adenocarcinoma

“…Belzutifan has been demonstrated to inhibit angiogenesis by attenuating the binding between Per-ARNT-Sim-B and HIF-2α [27].…”

“…Therefore, in the past decades, increasing numbers of antiangiogenic inhibitors targeting to these key regulators are constantly approved for clinical therapy, especially for those vessel-rich tumours [ 20 , 23 – 26 ]. Belzutifan has been demonstrated to inhibit angiogenesis by attenuating the binding between Per-ARNT-Sim-B and HIF-2α [ 27 ].…”

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

“…The PAS-B binding pocket on the HIF-2α contains a unique hydrophilic cavity that can accommodate a small molecule, which may result in a conformation change in HIF-2α and disruption of its interaction with ARNT [ 180 , 181 ]. Accordingly, HIF-2α small-molecule inhibitors are discovered, such as Belzutifan (Welireg™, MK-6482) [ 182 ] and PT2385 [ 183 ]. Despite the high sequence identity between HIF-2α and HIF-1α, these small-molecule inhibitors are highly selective in dissociating the HIF-2α/ARNT heterodimer while having no effect on HIF-1 function [ 181 , 184 ].…”