University of Virginia ETS Fusion Inhibitor Grant (Dr. John Bushweller)

ETS Fusion Small Molecule Inhibitor Grant

Recipient: John Bushweller, PhD - Professor, Chemical and Structural Biologist, University of Virginia

Focus Areas

Target: Develop small molecule inhibitor for ETS-driven cancers, specifically Ewing sarcoma
Focus Gene: EWS::FLI1 (EWSR1::FLI1) - transcription factor driving Ewing sarcoma

Scientific Challenge

"Undruggable" Targets:

• EWS::FLI1 is a transcription factor (TF) - notoriously difficult to drug
• Characterized as intrinsically disordered protein (IDP)
• Lacks known full structure, making traditional drug development impossible
• Acts as "ultimate recruiter" assembling proteins to promote tumor cell proliferation
• No direct targeted approaches available for this and similar TF-driven cancers (MYC, P53, ERG)

Dr. Bushweller's Novel Approach

Mechanism: Targeting Auto-Inhibition

• Exploits inherent biological process of auto-inhibition (cellular "checks-and-balance" system)
• Auto-inhibition acts as brake system stopping protein activity when no longer needed
• Strategy: Lock EWS::FLI1 in auto-inhibited state, preventing DNA binding and oncogenic function

Development Path:

1. Determined auto-inhibitory elements present and functional on FLI1 proteins ✅
2. Identified these auto-inhibitory domains as "druggable pockets" 🔥
3. Small molecule inhibitor can block EWS::FLI1 transcription factor activity 🏆

Research Foundation

Background from Prostate Cancer:

• Lab previously developed small-molecule inhibitor for ERG-driven prostate cancer (50% of prostate cancer patients)
• ERG and FLI1 are homologous (similar) - both in ETS subfamily
• Discovered inhibitor has scalability for both prostate and Ewing sarcoma without compromising efficacy

Grant-Funded Research

With LWF support, Bushweller lab will:

• Optimize current lead molecule for EWS::FLI1 (and ERG)
• Increase therapeutic potency
• Validate pharmacokinetics (stability) in vivo using mouse models
• If successful: Proceed to in vivo tumor testing
• Ultimate goal: Translate from bench to bedside for pediatric patients