Artemisinin-Proteasome Inhibitor Conjugates for the Treatment of Malaria and Multiple Myeloma

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

Figure 1: Artezomib induces apoptosis in multiple myeloma cells. Top: Treatment with HZ2083 increased Caspase-3/7 activity (associated with apoptosis) in an MM cell line comparable to clinically available proteasome inhibitor drugs. Bottom: Treatment with HZ2083 increased apoptosis-associated factors such as cleaved PARP, Chop, and p21.