Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that is activated in response to hypoxia and growth factors. HIF-1 plays a central role in tumor progression, invasion, and metastasis. Overexpression of the HIF-1 subunit has been observed in many human cancers and is associated with a poor prognostic outcome with conventional treatments. Targeting HIF-1 using novel small molecule inhibitors is, therefore, an attractive strategy for therapeutic development.
Before embarking on any drug discovery project, one of the fundamental questions to be answered is why a particular target is valid for therapeutic intervention. To satisfactorily answer this question, it is necessary to show that the target has a greater relevance in disease than in health. There are several lines of evidence to indicate that elevated levels of HIF-1 and its resultant activity promotes tumor progression and the development of treatment resistance. In addition, it has also been shown that inhibiting HIF-1 can reduce tumor growth in vivo. Accordingly, much interest has been generated in the search for HIF-1 inhibitors in recent years.
Chetomin, also known as Chaetomin is a mycotoxin (mold toxin), which as a metabolic product of fungi of the genus Chaetomium is created. It shows an antibiotic effect on gram-positive bacteria.
Chetomin is both a tumor growth inhibitor and a potent immunosuppressor. Antibacterial Mechanistic studies suggest that this compound inhibits the division and separation of cells in cultures of B. fibrisolvens D1. Additional experiments suggest that Chetomin has the ability to disrupt HIF (hypoxia-inducing factor) binding to the transcriptional coactivator p300. Disruption of HIF is believed to be done via a change in the structure of the CH1 domain of p300 which prevents interaction with HIF-1 and HIF-2. Inhibition of this interaction has been reported to attenuate hypoxia-inducible transcription.
Disrupting the ability of tumors to adapt to hypoxia may be an attractive antitumor strategy given the universality of hypoxia in solid tumors. Our prior studies demonstrated that attenuation of the HIF-1 pathway could be achieved through blockade of the interaction of p300/CBP with HIF-1 through the overexpression of a blocking polypeptide in tumor cells(Kung et al., 2000). Here, we describe our efforts to find a small molecule capable of blocking this nuclear protein-protein interaction. The primary candidate that emerged from a target-based HTS, chetomin, was found to indeed be able to block the interaction of HIF-1 and HIF-2 with p300 by disrupting the HIF-interacting domain of p300. This resulted in attenuation of hypoxia-inducible transcription in cell culture, as well as in vivo when systemically administered in mice.
- Available in both 1 mg and 5 mg sizes (A.G. Scientific product #C-1704)
- CAS Number: 1403-36-7
- Molecular Weight: 710.86
- Molecular Formula: C31H30N6O6S4
- Purity: >98%
- Physical Appearance: Off-white to fawn solid
- Solubility: Soluble in DMSO, ethyl acetate or pyridine; fairly soluble in methanol, 100% ethanol; insoluble in water.
- SMILES: CN1C(=O)C2(N(C(=O)C1(SS2)CC3=CN(C4=CC=CC=C43)C56CC78C(=O)N(C(C(=O) N7C5NC9=CC=CC=C69)(SS8)CO)C)C)CO
- Protect from light and moisture. Avoid freeze/thaw cycles.
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Children's Hospital, Boston, MA 02115 USA
- Novartis Pharmaceuticals Corporation, Oncology Department, Cambridge, MA 02139 USA
- Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115 USA
- Novartis Pharma AG Natural Products Unit/Discovery Technologies, Basel, Switzerland CH-4002
- AstraZeneca, Cancer Discovery, R & D Boston, Waltham, MA 02451 USA