1. Novel Transcription Factor Inhibitor as Treatment for Epithelial Cell Cancers
John Bushweller, Department of Molecular Physiology and Biological Physics, University of Virginia
Jeff James
Licensing Manager
UVA Licensing and Ventures Group

2. Value position
Novel small molecule inhibitors that are potent against breast, ovarian, and lung epithelial cancer cell lines and use a les exploited mechanism by targeting a transcription factor involved in cancer pathways
Transcription factor inhibition as treatment mechanism
Potent against epithelial cancer cell lines in vitro
Specific ablation of cancer cell and not normal cell lines in vitro
Potential for targeting of cancer stem cells
Compounds are orally bioavailability
Potentially low toxicity
Compounds target multiple cancer types

3. Market Respiratory Cancers: 67% mortality in US
Market expected to grow from $4 billion in 2010 to $13.5 billion by 2020
Breast Cancers: 18% mortality in US
Market expected to grow from $9.8 billion in 2013 to $18.2 billion by 2023
Ovarian Cancers: 67% mortality in US
Market expected to grow from $460 million in 2011 to $1.4 billion by 2021
Current treatments utilize monoclonal antibodies or small molecule inhibitors Pitfalls: Off target effects, toxicity, moderately effective, most converge on small number of biological pathways and downstream effectors, e.g. EGFR, Ras, PI3K, Her2
There is the need for more potent therapies that address other pertinent pathways involved in breast, ovarian and lung cancer progression
Source: World Cancer Research Fund, American Cancer Society, IMShealth, Markets&Markets, Decision Resources

4. Mechanism of action
CBFβ and RUNX1 are proteins that together to form Core Binding Factor, a transcription factor involved in cellular development
Compounds bind to CBFβ and block its interaction with RUNX proteins, abrogating downstream signaling events associated with cancer

5. Compounds Kill Epithelial Lung Cancer Cells but Not Normal Lung Cells
A) Active inhibitor reduces lung cancer cell viability to similar degree as staurosporine, a well-defined inducer of cell death, compared to treatment with DMSO and inactive control.
B) Active inhibitor has no deleterious effect on viability of normal lung cell line as compared to staurosporine treatment. B)
AI Active inhibitor
AI-4-88 Inactive control

6. CBFβ Inhibitor Ablates Viability of Ovarian
Cancer Cell Lines
Dose-dependent effect of AI inhibitor on ovarian cancer cell lines after 72 hours

7. Compounds are Effective Against Breast Cancer Cell lines in 3D Organotypic Culture
A) Brightfield microscopy of colony breast cancer cell line colony forming units (CFU) in 3D culture
B) Enumerated CFUs show active inhibitor reduces growth of cell line in 3D culture compared to control treatments. A) B)
Active inhibitor (AI-14-91, AI ) 1 µM
Inactive control (AI-4-88) 1 µM
AI is a derivative of AI with improved in vivo properties

8. CBFβ Inhibitors are Orally Bioavailable
: Plasma concentration as a
function of time for active inhibitors AI or AI-14-91
: concentration from oral gavage dosing
 : Concentration from intraperitoneal dosing
(100 mg/kg) in mice.
AI Intraperitoneal
AI Oral Gavage
AI Intraperitoneal
Half life (min)
179
203
243
AUC(0-inf) (µmol∙min/L)
8.14
2.22
2.08
Mean Residence Time (min)
74.6
180.4
90.6
Volume of Distribution (mL)
193.9
754.0
958.7
Clearance (mL/min)
0.75
2.57
2.74

9. Future Work We’re continuing development of the compounds:
Testing inhibitor efficacy in vivo, 6-8 months
Optimizing compounds – 6-12 months
Test toxicity of optimized compounds in vivo, months
UVa is currently searching for partners to continue developing these compounds as anti- tumor agents

10. UVa Licensing and Ventures Group
Contact:
Jeffrey A. James, Ph.D., CLP.
Licensing Manager
UVa Licensing and Ventures Group
722 Preston Ave., Ste. 107
Charlottesville, VA 22902
(434)  (direct)
(434)  (main)
(434)  (fax)