Chemical biology approach for the development of hypoxia inducible factor (HIF) inhibitor LW6 as a potential anticancer agent.

Intratumoral hypoxia has long been considered to be a driving force in tumor progression as well as a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for drug discovery and the development of targeted therapies in this field. LW6 represents an important new class of small molecules that inhibit HIF-1; it has been major source for diverse lead compounds including HIF-1α inhibitors. Through a chemical biology approach, LW6-derived chemical probes were successfully utilized for the identification of the direct targeting of a protein in cancer. LW6 provides a valuable platform for the discovery and development of small molecule inhibitors of HIF-1α-dependent tumor progression, metabolic reprogramming, and angiogenesis.