Using a Toxic RNA to Synthesize Its Own Inhibitor

Using a Toxic RNA to Synthesize Its Own Inhibitor Suzanne Rzuczek Ph.D. Disney Lab Department of Chemistry The Scripps Research InsDtute September 12, 2014 1 Precise Medicines Create Target-‐Speciﬁc Therapies Transcrip5on DNA Transla5on mRNA Disease-‐
Associated Protein 2 Examples of Precise Medicines Disease-‐Associated Protein is Not Made Transcrip5on DNA Transla5on An5sense Oligonucleo5des Speciﬁcally Inhibit Proteins (Gleevec) mRNA Disease-‐
Associated Protein 3 OpDmizing Precise Medicines 4 Healthy and Diseased Cells are Exposed to the Same Amount of Treatment Cellular CharacterisDcs of DM MBNL1 MBNL1 5 Techniques for Synthesizing Potent Molecules Inside of Diseased Cells N3
Lead Molecule AddiDon of Bioorthogonal Groups RNA Makes It’s Own Inhibitor 6 Rzuczek, et al. Angew. Chem. Int. Ed. Engl. 2014, in press DOI: 10.1002/anie.201406465 + K-Ak (5)
80
60
40
20
[Compound] (µM)
Rzuczek, et al. Angew. Chem. Int. Ed. Engl. 2014, in press DOI: 10.1002/anie.201406465 K-Ak (0.1)
-Ak (0.01)
Ak(0.001)
N3-K (10)
kK-Ak
(0.0001)
(10)
imer (10)
K-Aak(10)
imer (10)
-K-Aak
+ K-Ak (1)
(5)
-Aak (0.1)
Aak
(0.01)
-K-Ak
(10)
ak
(0.001)
3-K-Ak (1)
kK-Ak
(0.0001)
(0.1)
-Ak (0.01)
-Ak(0.001)
k (0.0001)
3
Rescue
BIN1
splicing % %
Rescue
of of
DM2 Pre-‐mRNA -K-Ak (10)
defect
Splicing D
efect -K-Ak (1)
Inhibitors Synthesized by RNA Targets Are Highly Potent ***
10
***
**
10 1 10-1 10-2 10-3 10-4
K-Aak(10)
-K-Aak (1)
-Aak (0.1)
Aak (0.01)
ak (0.001)
k (0.0001)
***
***
Potency ≈ **
1000 0
1 7 Future Studies Develop this technology for DM1 8 Acknowledgements •  Myotonic Dystrophy FoundaDon –  Molly White •  Dr. Ma_hew Disney •  Disney lab – 
– 
– 
– 
– 
– 
– 
Jessica Childs-‐Disney Sai Velagapudi Tuan Tran Wang-‐Yong Yang Yiling Luo Bala Vummidi Henry Wilson •  Collaborators – 
– 
– 
– 
– 
Charles Thornton Zhen-‐Zhi Tang Hajeung Park Yu Gao Thomas Kodadek 9

Download Report