Poster abstracts

Poster number 2 submitted by Katryna Cisek

Computational design of STAT3 inhibitors for targeted anti-cancer therapy

Katryna Cisek (Biophysics program, The Ohio State University), Deepak Bhasin, Nicholas Regan (Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University), Lauren Friedman, Matthew Sobo (Center for Childhood Cancer, Columbus Childrens Research Institute), Jiayuh Lin (Center for Childhood Cancer, Columbus Childrens Research Institute), Tom P.-K. Li (Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University), Chenglong Li (Biophysics program, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University)

Abstract:
Deregulation of the Jak/STAT pathway has been observed in many primary tumors, leading to an increase in angiogenesis and proliferation of various cancers. One member in this pathway, signal transducer and activator of transcription 3, or commonly called STAT3, is a validated downstream target protein². To this effect, the objective of our study is the inhibition of the STAT3 constitutive activation. Current strategies include peptidomimetics for STAT3 dimerization inhibition, platinum compounds blocking STAT3 binding with DNA, natural product derivatives and small synthetic molecule inhibitors⁵. Based on an existing inhibitor STA-21⁴, we have computationally re-designed novel compounds called LLL-3, LLL-7.3 and LLL-12. Even though these new compounds are STA-21 analogs, they offer two improved molecular features: 1) easy synthetic chemistry and large potential for derivation to a chemically diverse yet structurally focused library; 2) better biological activities. In AutoDock4³, LLL-3 is -6.8 kcal/mol with 10% docked conformation confidence, LLL-7.3 is -9.2 kcal/mol with 14% docked conformation confidence and LLL-12 is -8.1 kcal/mol with 17% docked conformation confidence. To date, the LLL compounds have proven to be more potent than STA-21 upon testing on several breast, prostate, brain, bladder, childhood cancer and leukemia cell lines¹. We have since computationally designed more derivatives, which are currently being synthesized for experimental testing.

References:
1. Bhasin D., et al. (2008) Bioorg Med Chem Lett. 18(1), 391 - 395.
2. Darnell, J E Jr. (2005) Nature Medicine. 11, 595 - 596.
3. Huey, R, et al. (2007) J Comput Chem. 28, 1145-1152.
4. Song, H., et al. (2005) Proc Natl Acad Sci U S A. 102(13), 4700 - 4705.
5. Yu H, et al. (2004) Nat Rev Cancer. 4(2), 97 - 105.


K.C. and C.L. acknowledge the HPC support from the Ohio Supercomputer Center.
This research is supported by the James S. McDonnell Foundation.

Keywords: STAT3, small molecule inhibitor, molecular docking