Inventors: Bhaskar Das, PhD Todd Evans, PhD

1. Boron containing oxadiazole based retinoids as novel therapeutic and diagnostic agents for AD and cancer Inventors: Bhaskar Das, PhDTodd Evans, PhD Department of Surgery Weill Cornell Medical College

2. What we have • Novel boron-containing retinoids • Uses: • PET/SPECT imaging • Therapeutics for: • Alzheimers • Cancer • Cancer, as Boron Neutron Capture Therapy agents

3. Rationale • Ding et al., 2008 showed, using APPswe/PS1 mouse, that systemic all-trans-RA administration reduced plaque, APP C-terminal fragments, and Tau and CDK5 phosphorylation, decreased reactive astrocytes and GFAP levels and improved learning and memory deficits in the Morris water maze. • Jarvis et al., 2010 used the Tg2576 mouse and a RARα agonist, and found increased extracellular APPsβand decreased the amounts of Aβ 1-40 and Aβ 1-42 in the cortex, via αsecretase ADAM10. • Donmez et al Cell. 2010 found that overexpressing SIRT1 in APPswe/PSEN1dE9 mice reduced plaques, reduced corticalGFAP reactivity, a reduction in Aβ1-42, increased ADAM10, and behavioral improvements in a fear-conditioning test and Morris water maze was revealed. It was further shown that SIRT1 activates transcription of ADAM10 by deacetylating the RARβ receptor – was done in embryonic fibroblasts rather than neurons.

4. 1) Alkene spacers are prone to cis-trans isomerization, which can reduce the specificity and increase toxicity. So introduced oxadiazole based group to protect cis-trans isomerization and increase water solubility. 2) The hydrophobic cyclohexane ring is prone to oxidation by CYP 450, CYP26 enzymes, so to reduce that, we introduced constrained phenyl and biphenyl compounds. 3) In place of the acid group we introduced boronic acid group as bio-isosters of acid group.

6. E. coli cells expressing Aβ42-GFP

7. Drosophila expressing the human Aβ42 gene in CNS neurons

8. Developmental status • POC established in flies • Synthesis established • Intellectual Property • Provisional filed • Next steps • Therapeutics – continue synthesizing and screening to develop more potent compounds • Imaging – need to achieve POC then begin screening for best compounds

9. Contact: Bruce Toman, CLP Technology Commercialization and Liaison Officer CCTEC 418 E 71st Street, Suite 61 New York, NY 10021 ph: 212-746-6187 toman@cornell.edu