Available Technology
Natural product avrainvillamide and its analogs as targeted anticancer agents
Technology:
Avrainvillamide
Markets Addressed
In vitro and in vivo validation:
In the NCI 60 cancer cell assay, an avrainvillamide analog has exhibited specific growth inhibition at near nanomolar levels against myeloma, and hence supports a likely biomarker strategy aimed at patient pre-selection. Avrainvillamide and this analog were advanced into colorectal cancer xenograft studies. Pharmacokinetics and maximum dose tolerability studies are in progress to prepare for pre-clinical testing in animal models.
The avrainvillamide program is, as yet, uncommitted to industry. Harvard seeks a licensing partner or a long-term alliance with a company offering leading competencies in anticancer therapy development. A long-term relationship is sought with the company best able to demonstrate its capabilities and commitment to the area.
Innovations and Advantages
Organic chemists at Harvard University led by Prof. Andrew Myers have a longstanding interest in the synthesis of structurally and biologically interesting anticancer agents of natural origin. The Myers’ laboratory has pioneered the total synthesis of the antiproliferative agent avrainvillamide, a compound originally isolated in trace quantities from marine fungi.
• First-in-class targeted agents with nanomolar GI50 in many cell lines
• Compounds validated by NCI 60 cancer cell assay and mouse xenograft model
• Novel cancer target that is overexpressed in multiple cancers; modulates p53 and c-Myc
• May be opportunity to develop patient preselection biomarker strategy
• Total synthesis of avrainvillamide and simplified analogs with SAR data
Avrainvillamide and analogs: First-in-class nucleophosmin inhibitors:
Using avrainvillamide as a lead structure, the Myers group has successfully synthesized ~130 avrainvillamide analogs with simplified structures, and some achieve comparable potency to the parent molecule. Through the support of the Harvard Accelerator Fund, the Myers group has made considerable progress on the optimization of the synthesis and scale-up production of the compounds. Our chemists have generated structure activity relationship (SAR) data that will be invaluable for the design of potential drug leads. Computer models of avrainvillamide-nucleophosmin interaction have also been used to fine-tune the design of the analogs.
Nucleophosmin: Novel and selective oncology target:
The Myers group has shown that avrainvillamide interacts directly with the pro-oncogenic protein nucleophosmin (NPM) in cancer cells. Nucleophosmin is a nucleolar phosphoprotein that shuttles between the nucleus and cytoplasm, and has a critical role in cell proliferation and cell death. NPM expression is tightly regulated during cell proliferation and is overexpressed in several types of cancer. It is implicated in the regulation of the tumor suppressors ARF and p53, and most recently, the proto-oncogene c-Myc. Overexpression of NPM dramatically stimulates c-Myc-induced hyperproliferation and oncogenic activities (PNAS 2008, 105, 18794-18799). NPM is also a major regulator of ribosome biogenesis. Upon growth factor stimulation, NPM forms a protein complex with the serine/threonine protein kinase Akt, together they regulate cell cycle progression and cell survival (PNAS 2008, 105, 16584-16589).
Because nucleophosmin is overexpressed in tumor cells, compounds which exert their function predominantly by binding to nucleophosmin have the potential to be selective anticancer agents by inhibiting tumor growth without harming healthy tissue. In assays developed in the Myers’ laboratory, avrainvillamide has shown a 10-fold selective toxicity against human melanoma cells over non-cancerous fibroblast cells from the same donor.
Additional Information
Intellectual Property: Harvard University believes in vigorous protection of its intellectual property. Multiple patent applications have been filed covering processes to synthesize avrainvillamide and its derivatives, compound use claims, and novel compositions of matter.
Publications:
-Identification of a Novel Michael Acceptor Group for the Reversible Addition of Oxygen- and Sulfur-Based Nucleophiles. Synthesis and Reactivity of the 3-Alkylidene-3H-indole 1-Oxide Function of Avrainvillamide. Andrew G. Myers and Seth G. Herzon, J. Am. Chem. Soc. 2003, 125, 12080. This publication is available in Adobe PDF.
-Enantioselective Synthesis of Stephacidin B. Seth G. Herzon and Andrew G. Myers, J. Am. Chem. Soc. 2005, 127, 5342. This publication is available in Adobe PDF.
-Evidence for the Rapid Conversion of Stephacidin B into the Electrophilic Monomer Avrainvillamide in Cell Culture. Jeremy E. Wulff, Seth B. Herzon, Romain Siegriest and Andrew G. Myers, J. Am. Chem. Soc. 2007, 129, 4898. This publication is available in Adobe PDF.
-The Natural Product Avrainvillamide Binds to the Oncoprotein Nucleophosmin. Wulff JE, Siegrist R, Myers AG. J Am Chem Soc. 2007, 129, 14444. This publication is available in Adobe PDF.
Download the Opportunity Statement here.
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Inventor(s):
Chan, Kok Ping
Herzon, Seth B
Myers, Andrew G.
Nising, Carl Friedrich
Siegrist, Romain
Svenda, Jakub
Wulff, Jeremy Earle
Zajac, Matthew Allen
Categories:
For further information, please contact:
Vivian Berlin, Director of Business Development
(617) 496-0474
Reference Harvard Case #2438