1.Chemical biology approach for the development of hypoxia inducible factor (HIF) inhibitor LW6 as a potential anticancer agent.
Naik R1, Han S1, Lee K2. Arch Pharm Res. 2015 Sep;38(9):1563-74. doi: 10.1007/s12272-015-0632-5. Epub 2015 Aug 27.
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.
2.LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells.
Sato M1, Hirose K1, Kashiwakura I2, Aoki M1, Kawaguchi H1, Hatayama Y1, Akimoto H1, Narita Y1, Takai Y1. Mol Med Rep. 2015 Sep;12(3):3462-8. doi: 10.3892/mmr.2015.3862. Epub 2015 May 27.
Hypoxia‑inducible factor 1 (HIF‑1) activates the transcription of genes that act upon the adaptation of cancer cells to hypoxia. LW6, an HIF‑1 inhibitor, was hypothesized to improve resistance to cancer therapy in hypoxic tumors by inhibiting the accumulation of HIF‑1α. A clear anti‑tumor effect under low oxygen conditions would indicate that LW6 may be an improved treatment strategy for cancer in hypoxia. In the present study, the HIF‑1 inhibition potential of LW6 on the growth and apoptosis of A549 lung cancer cells in association with oxygen availability was evaluated. LW6 was observed to inhibit the expression of HIF‑1α induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel‑Lindau protein. In addition, at this concentration, LW6 induced hypoxia‑selective apoptosis together with a reduction in the mitochondrial membrane potential. The intracellular reactive oxygen species levels increased in LW6‑treated hypoxic A549 cells and LW6 induced a hypoxia‑selective increase of mitochondrial O2•‑.
3.HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1.
Kim BS1, Lee K2, Jung HJ3, Bhattarai D2, Kwon HJ4. Biochem Biophys Res Commun. 2015 Feb 27;458(1):14-20. doi: 10.1016/j.bbrc.2015.01.031. Epub 2015 Jan 17.
Hypoxia inducible factor-1 alpha (HIF-1α) plays an important role in angiogenesis and metastasis and is a promising therapeutic target for the development of anti-cancer drugs. We recently developed a new synthetic small molecule inhibitor of HIF-1α, LW6, which results in inhibition of angiogenesis. To investigate its underlying mechanism, target protein identification was conducted by reverse chemical proteomics using phage display. We identified calcineurin b homologous protein 1 (CHP1) as a target protein of LW6, which specifically binds to CHP1 in a Ca(2+) dependent manner. Covalent labeling of LW6 using photoaffinity and click chemistry demonstrated its co-localization with CHP1 in live cells. HIF-1α was decreased by CHP1 knockdown in HepG2 cells, and angiogenesis was not induced in HUVEC cells by treatment with conditioned media from CHP1 knockdown cells compared to the control. These data demonstrated that LW6 inhibited HIF-1α stability via direct binding with CHP1 resulting in suppression of angiogenesis, providing a new insight into the role of CHP1 in HIF-1α regulation.