42
6-Ethylthioinosine for the Treatment of Cancers that Overexpress Adenosine Kinase (ADK)
Weill Cornell Medicine
Small molecule
Oncology
Hit To Lead or Lead Optimization
Background
• The γ-herpesvirus KSHV, also called HHV-8, is the etiological agent of Kaposi’s sarcoma (KS), multicentric Castleman’s disease, and primary effusion lymphoma (PEL)
• KS, the most common malignancy in AIDS patients, is often treatable by antiviral therapy and radiation or chemotherapy
• PEL is a rare HIV-associated non-Hodgkin’s lymphoma (NHL) that is largely a highly aggressive and intractable disease, with rapid progression to death
Unmet Needs
Specific and effective therapeutics for diseases caused by KSHV
Technology Overview
• Identification of 6-ethylthioinosine (6-ETI) as a potent inhibitor of cancers that overexpress adenosine kinase (ADK)
• 6-ETI was identified through a high throughput screen of compounds that selectively inhibit NF-κB in a KSHV-infected PEL cell line (LC50=50nM)
• The inventors then demonstrated that 6-ETI is converted into phosphor-6-ETI by ADK, which is commonly overexpressed in several cancers
• 6-ETI is highly effective in both PEL and disseminated multiple myeloma (MM) xenograft mouse models, with significant reduction in tumor burden and prolonged survival
• 6-ETI was also demonstrated to be effective against solid tumors that overexpress ADK, including those
with resistance to 1L therapies
• 6-ETI is therefore a promising lead compound for targeted treatment of ADK positive cancers
Ethal Cesarman, J. David Warren
PCT-US2017-027590 (2017.04.14)
Patent Family: US
"Identification of a nucleoside analog active against adenosine kinase–expressing plasma cell malignancies". Nayar, U. et al. Journal of Clinical Investigation 2017, 127(6), 2066–2080
