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.
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.
|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|
|Han, Xu; Chen, Chun-Chi; Kuo, Chih-Jung et al. (2015) Crystal structures of ligand-bound octaprenyl pyrophosphate synthase from Escherichia coli reveal the catalytic and chain-length determining mechanisms. Proteins 83:37-45|
|Sinko, William; Wang, Yang; Zhu, Wei et al. (2014) Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads. J Med Chem 57:5693-701|
|Li, Kai; Schurig-Briccio, Lici A; Feng, Xinxin et al. (2014) Multitarget drug discovery for tuberculosis and other infectious diseases. J Med Chem 57:3126-39|
|Liu, Wenting; Feng, Xinxin; Zheng, Yingying et al. (2014) Structure, function and inhibition of ent-kaurene synthase from Bradyrhizobium japonicum. Sci Rep 4:6214|
|Oldfield, Eric; Feng, Xinxin (2014) Resistance-resistant antibiotics. Trends Pharmacol Sci 35:664-74|
|Shang, Na; Li, Qian; Ko, Tzu-Ping et al. (2014) Squalene synthase as a target for Chagas disease therapeutics. PLoS Pathog 10:e1004114|
|Aripirala, Srinivas; Gonzalez-Pacanowska, Dolores; Oldfield, Eric et al. (2014) Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates. Acta Crystallogr D Biol Crystallogr 70:802-10|
|Liu, Yi-Liang; Lindert, Steffen; Zhu, Wei et al. (2014) Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site. Proc Natl Acad Sci U S A 111:E2530-9|
|Zhang, Yonghui; Zhu, Wei; Liu, Yi-Liang et al. (2013) Chemo-Immunotherapeutic Anti-Malarials Targeting Isoprenoid Biosynthesis. ACS Med Chem Lett 4:423-427|
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