Abstract

Protein-protein Interactions (PPIs) play critical roles in biological processes that can propagate or terminate llfe.These PPIs have been Implicated In numerous disease states, including HIV, diabetes, and cardiovascular and neurodegenerative diseases, making them Important targets for dIsruptlon.Often recognition between proteins is mediated by protein secondary structures, such as a-helices, via one helical face, where interacting residues occupy predominantly the /, / + 3 or / + 4, and / + 7 positions. Accordingly, these surfaces are critical targets for small molecule mimicry. Our previous focus has yielded a-helix mimetics with Inherent disadvantages, either poor solubility (terphenyl and terpyridine scaffolds) or hydrogen-bonding networks to maintain their correct orientation (terephthalamide and thspyrldylamlde scaffolds). As a mechanism to overcome the disadvantages of our previous designs, we have reported an Innovative scaffold that replaces the terminal six-membered aromatic end units with water-soluble five-membered heterocyclic groups.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067771-15
Application #
7882864
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (J1))
Project Start
2009-05-01
Project End
2010-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
15
Fiscal Year
2009
Total Cost
$309,319
Indirect Cost

  Institution

Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612

  Publications

Patel, R A; Liu, Y; Wang, B et al. (2014) Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 33:550-5
Vigil, Dominico; Kim, Tai Young; Plachco, Ana et al. (2012) ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res 72:5338-47
Li, Rongshi; Martin, Mathew P; Liu, Yan et al. (2012) Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J Med Chem 55:2474-8
Pireddu, Roberta; Forinash, Kara D; Sun, Nan N et al. (2012) Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm 3:699-709
Mitin, Natalia; Roberts, Patrick J; Chenette, Emily J et al. (2012) Posttranslational lipid modification of Rho family small GTPases. Methods Mol Biol 827:87-95
Patel, Ronil A; Forinash, Kara D; Pireddu, Roberta et al. (2012) RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res 72:5025-34
Neel, Nicole F; Martin, Timothy D; Stratford, Jeran K et al. (2011) The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery. Genes Cancer 2:275-87
Berndt, Norbert; Sebti, Saïd M (2011) Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors. Nat Protoc 6:1775-91
Cook, Danielle R; Solski, Patricia A; Bultman, Scott J et al. (2011) The ect2 rho Guanine nucleotide exchange factor is essential for early mouse development and normal cell cytokinesis and migration. Genes Cancer 2:932-42
Berndt, Norbert; Hamilton, Andrew D; Sebti, Saïd M (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11:775-91

Showing the most recent 10 out of 117 publications