The objective of this work is to develop novel anti-cancer drugs that target, primarily, isoprenoid biosynthesis. The work builds on the discovery in several recent clinical trials that the bisphosphonate drug zoledronate has unexpected positive effects as an adjuvant (in combination therapy with aromatase inhibitors) in breast cancer, reducing the re-occurrence of disease (at any site) by 36%, in addition to increasing the survival of prostate cancer patients. Likely targets are direct tumor cell killing, inhibition of invasiveness and angiogenesis, and """"""""phenotype switching"""""""" (34 T cell activation and conversion of tumor associated macrophages (TAMs) from a pro-tumor, M2, to an anti-tumor, M1, phenotype). In the work proposed here we will test the hypothesis that a new class of bisphosphonates called """"""""lipophilic bisphosphonates"""""""" (LBPs) will be far more effective than zoledronate in tumor cell killing and in 34 T cell activation and that they will also switch macrophages from M2 ->M1, resulting in new leads for cancer chemotherapy and immunotherapy. We also propose to test the hypothesis that by using a combination of high-field solid-state NMR and calorimetry to develop molecular models for bone-ligand interactions, we can very effectively design other anti-cancer drugs that bind to bone, realizing the long sought after goal of """"""""magic bullets"""""""" for bone diseases.
In Aim 1, we will develop compounds that inhibit two prenyl synthase enzymes: farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), that are involved in protein (e.g. Ras, Rho, Rap1A) prenylation, of importance in cell signaling and cell survival pathways.
In Aim 2, we will carry out cell-based and in vivo testing of the compounds made in Aim 1.
In Aim 3, we will develop the concept of """"""""bone-tags"""""""" or """"""""magic bullets"""""""", compounds which enable the delivery of drugs to bone. If successful, we will thus develop completely new approaches to cancer chemotherapy and immunotherapy that, in the future, will have a major impact in the clinic.

Public Health Relevance

The project is aimed at developing new leads for treating cancer. Focus is on the development of a new generation of drugs;lipophilic bisphosphonates that kill tumor cells, as well as activate 34 T cells and macrophages, to kill tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158191-02
Application #
8269817
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2011-06-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$316,099
Indirect Cost
$108,599
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Liu, Meixia; Chen, Chun-Chi; Chen, Lu et al. (2016) Structure and Function of a ""Head-to-Middle"" Prenyltransferase: Lavandulyl Diphosphate Synthase. Angew Chem Int Ed Engl 55:4721-4
Yang, Yunyun; Ko, Tzu-Ping; Chen, Chun-Chi et al. (2016) Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets. ACS Chem Biol 11:1362-71
Desai, Janish; Wang, Yang; Wang, Ke et al. (2016) Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth. ChemMedChem 11:2205-2215
Wang, Yang; Desai, Janish; Zhang, Yonghui et al. (2016) Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase. ChemMedChem 11:2311-2319
Li, Jikun; Feng, Xinxin; Zhu, Wei et al. (2016) Chemical Exchange Saturation Transfer (CEST) Agents: Quantum Chemistry and MRI. Chemistry 22:264-71
Zhang, Lilan; Chen, Chun-Chi; Ko, Tzu-Ping et al. (2016) Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5. Angew Chem Int Ed Engl 55:4716-20
García-García, Verónica; Oldfield, Eric; Benaim, Gustavo (2016) Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109. Antimicrob Agents Chemother 60:6386-9
Desai, Janish; Liu, Yi-Liang; Wei, Hongli et al. (2016) Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase. ChemMedChem 11:1915-23
Kim, Meekyum Olivia; Feng, Xinxin; Feixas, Ferran et al. (2015) A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery. Chem Biol Drug Des 85:756-69
Yang, Gyongseon; Zhu, Wei; Wang, Yang et al. (2015) In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei. ACS Infect Dis 1:388-98

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