Value Proposition
· Itraconazole is in clinical trials for cancer treatment as it is known to have antiangiogenic activity and anti-Hedgehog pathway activity, but its use has been limited by its potent inhibition of the drug metabolizing enzyme CYP3A4
· The designed analog for itraconazole has greater antiangiogenic potency without CYP3A4 inhibition and therefore may achieve therapeutic effect with fewer side effects.
· The designed analog is a promising angiogenesis inhibitor that can be used in combination with other known anti-cancer drugs.
Unmet Need
· Targeted therapies treat cancer by interfering with specific proteins and pathways that help tumors grow and spread throughout the body.
· Current small molecule targeted therapies, including those that block angiogenesis or Hedgehog activity, are limited in their potency.
· The use of itraconazole in the treatment of cancer has been limited by its potent inhibition of the drug metabolic enzyme cytochrome P450 3A4 (CYP3A4) which causes drug-drug interactions.
· Tumors may develop drug resistance against a targeted therapy and higher doses produce greater side effects.
· Patients experience high rates of side effects that may lead to treatment interruption or cessation.
· Therefore, there is strong need for analogs to be developed to target validated pathways at a higher potency without inhibiting CYP3A4 or producing other side effects.
Technology Description
· Angiogenesis, the process of forming new blood vessels, is a critical factor in the development and spread of cancerous tumors.
· Itraconazole is a small molecule drug that has previously been found to have antiangiogenic activity and anti-Hedgehog pathway activity and is currently being clinically tested as a cancer therapeutic.
· Researchers at Johns Hopkins have developed several analogs for itraconazole that have greater antiangiogenic potency and can be modified to differentially affect the inhibition of HUVEC proliferation and Hedgehog signaling.
Stage of Development
Preclinical proof-of-concept
Data Availability
Data available in the publications linked below.
Publications
Li Y, Pasunooti KK, Li RJ, Liu W, Head SA, Shi WQ, Liu JO. Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition. J Med Chem. 2018 Dec 27;61(24):11158-11168. doi: 10.1021/acs.jmedchem.8b01252. Epub 2018 Dec 10. PMID: 30481027.
Shi W, Nacev BA, Aftab BT, Head S, Rudin CM, Liu JO. Itraconazole side chain analogues: structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling. J Med Chem. 2011 Oct 27;54(20):7363-74. doi: 10.1021/jm200944b. Epub 2011 Oct 5. PMID: 21936514; PMCID: PMC3307530.
