Troy Messick (The Wistar Institute, USA)
“Development of an EBNA1 Inhibitor for the Treatment of NPC: Toward First-in-Human Studies”
- EBNA1 is master regulator of ENBV latency
- ENA1 is the only viral protein expressed in all EBV cancers
- EBNA1 is required for cell transformation and tumorigenesius
- EBNA1 structure is now and druggable
- No EBNA1 orthologs in human proteome predicates a high therapeutic index
- EBNA1 is a druggable target selected 100 fragments, soaked 5 compounds for each crystal
- Collected data
- Candidate selection campaign
- – 90+high quality structure
- Biochemical assay IC50=299 nM
- VK1727, VK
- Xenografts (NSG). VK-2019 10 mpk IP
- C666-1
- MutiLCL
- C15-PDX NPC (Morocco)
- C17-PDX NPC ()
- VK-2019 is effective in NPC-PDX
- 3 mpk, 30, 100 mpk
- Combination of VK2019 and RT (radiotherapy)
- Target engagement studies
- – TGFb are affected by treatment
- – EBV qPCR for C15-PDX (EBNA1 and Bam-HI W
- – EBER-ISH time course expertment
- – Toxicology studies prior to IND
- – Maximum tolerated does (MTD)
- – Dose range finding
- Summary
- – no toxicology findings that preclude further development
- – Observe excellent exposure
- – No severe toxicity observed
- Exposure summary
2016 GRC NPC
Troy Messick (The Wistar Institute, USA) “Development of Small Molecule Inhibitors of EBNA1 for the Treatment of Nasopharyngeal Carcinoma” (Tuesday Poster # 18)