Development of small molecule inhibitors of hypoxia-inducible factors for cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hypoxia-inducible factors (HIFs), specifically HIF-1 and HIF-2, are key regulators of gene transcription involved in cancer progression.
• Inhibition of HIF activity has demonstrated efficacy in blocking tumor growth, angiogenesis, and metastasis in preclinical cancer models.

Purpose of the Study:

• To review the therapeutic potential of small-molecule inhibitors targeting HIF-1 and HIF-2 in cancer treatment.
• To highlight the significance of HIF inhibitors as a novel therapeutic strategy, particularly in combination therapies.

Main Methods:

• Review of preclinical studies on small-molecule HIF inhibitors.
• Analysis of clinical data for approved HIF inhibitors like belzutifan.
• Discussion of the development of dual HIF-1/2 inhibitors and their potential applications.

Main Results:

• Small-molecule HIF inhibitors exhibit antitumor activity in various mouse models.
• Belzutifan, an HIF-2 inhibitor, is approved for renal cell carcinoma treatment.
• Dual HIF-1/2 inhibitors are under development and show promise for cancer therapeutics.

Conclusions:

• HIF inhibitors represent a significant advancement in cancer therapy.
• Combination of HIF inhibitors with existing treatments, including immune checkpoint blockade, may enhance patient survival across multiple cancer types.