Principal Investigator:
Gang Lin, Associate Professor of Research in Microbiology and Immunology
Background & Unmet Need
- Malaria
With over 200 M cases annually and 500 K deaths, mostly in children, malaria remains a persistent global health crisis - Plasmodium falciparum (Pf) has developed resistance to all currently available antimalarials, including the artemisinins (ARTs), a key therapy
- ART is a pro-drug converted to radicals within the parasites, causing oxidative damage that overload the parasites’ ubiquitin-proteasome degradation system (UPS)
- However, ART resistance is spreading in Southeast Asia and has also been reported in Africa
- Unmet Need: Novel antimalarials as components of combination therapy to prevent further dissemination of ART resistance
- Multiple Myeloma
- Worldwide, there are ~86 K new multiple myeloma (MM) patients and ~63 K related deaths each year
- Proteasome inhibitor drugs are standard of care for the treatment of MM, but only have a response rate of ~25% when used as single agents
- Almost all MM patients using proteasome inhibitor treatment will relapse due to a variety of resistance pathways, including mutations in the proteasome subunit 19S
- Artemisinin and its analogues are clinically used to treat Malaria, but may also be promising cancer therapeutics as they demonstrate potent antineoplastic activity
- Unmet Need: Improved proteasome inhibitors for multiple myeloma and other cancers which overcome resistance mechanisms
Technology Overview
- Malaria
- The Technology: ART and Pf20S inhibitor hybrids (Artezomibs, ATZs) as dual mechanism therapies for the treatment of wild type and resistant Pf strains
- The inventors first demonstrated that conjugation of an ART moiety to a proteasome inhibitor did not interfere with the binding and inhibition of Pf20S
- The inventors then designed four new ATZs, in which the artesunate analog WZ-1840 is conjugated to a proteasome inhibitor via a propionate linker
- PoC Data: In growth inhibition assays of Pf Dd2 and two proteasome inhibitor-resistant strains, the ATZs substantially overcame resistance to the proteasome inhibitor moiety alone conferred by Pf20s point mutations
- The ATZs demonstrated ~5x improvement for Dd2 mutant β6A117D and ~100x improvement for Dd2 mutant β5A49S compared to the proteasome inhibitor WZ-1839 alone
- Multiple Myeloma
- The Technology: Artemisinin and proteasome inhibitor hybrids (Artezomibs, ATZs) for treatment of human cancers, including multiple myeloma
- The inventors have designed a series of Artezomibs, wherein Artemisinin analog Artesunate is conjugated to a proteasome inhibitor via a linker
- Artemisinin is known to cause degradation of Ferritin, which may in turn cause Ferroptosis, an iron-dependent programed cell death
- The longer, peptide-based proteasome inhibitors may overcome the resistance conferred via the mutations in proteasome subunits
- PoC Data: Proteasome inhibition assays demonstrated inhibitory activity of the Artezomibs against a variety of proteasome subunits
- Artezomibs demonstrated cytotoxicity against a panel of multiple myeloma cell lines, including MM.1S, CAG, and RPMI8226
Technology Applications
- Malaria
- Treatment and prevention of malaria infection
- Combination therapy to overcome ART resistance
- Strategy for the direct conjugation of other compound with anti-malarial activity
- Multiple Myeloma
- Treatment of multiple myeloma, either alone or in combination with other proteasome inhibitors
- Therapeutic for other cancers susceptible to proteasome inhibition, such as pancreatic, head and neck cancer, and non small cell lung carcinoma
Technology Advantages
- Malaria
- Conjugate approach combines two MOAs in a single compound (artemisinins and proteasome inhibitors)
- Overcomes Pf treatment resistance to individual therapies
- Therapeutic activity of each moiety is preserved
- Multiple Myeloma
- Artezomibs can be tailored to inhibit one or more proteasome subunits
- Artezomibs show high potency in vitro
- Therapeutic activity of each moiety is preserved
Publications
Intellectual Property
Patents
- PCT Application Filed: WO2022159581A2. "Artemisinin-proteasome inhibitor conjugates and their use in the treatment of disease." Published Jul 28, 2022.
- US Application Filed
- EP Application Filed
Cornell Reference
- 9516
Contact Information
For additional information please contact
Jamie Brisbois
Manager, Business Development and Licensing
Phone: (646) 962-7049
Email: jamie.brisbois@cornell.edu