The objective of the proposed research is to discover and develop new classes of anti-breast cancer agents from higher plants, which have been and still remain a significant source of new drugs. We will identify structurally unique hits from rare sources of plants, particularly rainforest extracts with confirmed cytotoxic activity as screened b the National Cancer Institute, as well as medicinal plants used for cancer-related therapy. Lead compounds, optimized using medicinal chemistry approaches, will be subjected to critical preclinical in vivo assessment, not only with conventional xenograft mouse models, but also with an innovative and unique genetically engineered spontaneous breast cancer mouse model having conditional mutations on tumor suppressor genes Brca1 and p53. Furthermore, we will explore possible mechanism(s) of action based on chemical profiling and effects on responsible pathways, including sex steroid receptors, cell cycle arrest, kinase inhibition, or signal transduction pathways. The overall goals of our program are to identify and develop clinical trial candidates, especially for treating breast cancers. The following specific studies will be carried out to accomplish our goals.
Specific Aim -1: In vitro screening and bioactivity-directed fractionation and isolation to identify breast cancer-selective compounds starting from plant extracts with confirmed activity and counter-screened in-house on the basis of susceptibility to breast cancer cell lines.
Specific Aim -2: New lead optimization using synthetic modifications to improve pharmacological profile. Structural characterization of new active leads (Aim 1) and modified compounds (Aim 2) will be accomplished by chemical, physical, and spectroscopic techniques.
Specific Aim -3: Two-step in vivo evaluations to confirm activity in mouse models, both conventional xenograft mouse models and innovative breast cancer Brca1/p53-Crec mouse model.
Specific Aim -4: Mechanism of action studies to identify druggable targets and compounds for breast cancer treatment. Advantages of our program include 1) an excellent supply of highly active lead compounds and promising cytotoxic plant species, including rainforest species from the NCI Natural Product Repository Program, (2) excellent productivity in isolation and structural modification of new leads with new mechanisms of action as clinical trials candidates, which in turn could lead to innovative methods for cancer chemotherapy, and (3) superior prospects for the successful development of a clinically useful drug, based on promising in vivo results with neo-tanshinlactone analogs against breast cancers. An emphasis of our study will be on finding optimal analogs from these different compound classes to advance to anticancer clinical trials during the next grant period.
New drugs are continually needed to treat various types of cancer, particularly breast cancer, as a woman in the US has about a 12% chance of getting breast cancer in her lifetime, and a woman who has heterozygously inherited the mutant breast cancer susceptibility gene (BRCA1 or BRCA2) can have up to a 60-90% risk of being diagnosed with breast cancer. With the use of an innovative double conditional knockout mouse (Brca1f11/f11p53f5&6/f5&6WAPCrec) that mimics human breast cancer, we will be able to successfully discover new anticancer drug candidates from novel active constituents of medicinal plants, especially from unique rainforest species, which are disappearing rapidly. These lead compounds can be optimized through synthetic modification, as seen with our new neo-tanshinlactone analogs that have already shown promising results in this mouse model and will also be a focus of this research program.
|Wang, Song; Li, Rui-Juan; Zhu, Rong-Xiu et al. (2014) Notolutesins A-J, dolabrane-type diterpenoids from the Chinese liverwort Notoscyphus lutescens. J Nat Prod 77:2081-7|
|Hung, Hsin-Yi; Nakagawa-Goto, Kyoko; Tokuda, Harukuni et al. (2014) A-ring modified betulinic acid derivatives as potent cancer preventive agents. Bioorg Med Chem Lett 24:1005-8|
|Shi, Li-Shian; Kuo, Sheng-Chu; Sun, Han-Dong et al. (2014) Cytotoxic cardiac glycosides and coumarins from Antiaris toxicaria. Bioorg Med Chem 22:1889-98|
|Liu, Wei-Ting; Chen, Ching; Lu, I-Chen et al. (2014) MJ-66 induces malignant glioma cells G2/M phase arrest and mitotic catastrophe through regulation of cyclin B1/Cdk1 complex. Neuropharmacology 86:219-27|
|Yu, Fang-Lin; He, Xiao-Yang; Gu, Chunping et al. (2014) Discovery of novel antitumor dibenzocyclooctatetraene derivatives and related biphenyls as potent inhibitors of NF-*B signaling pathway. Bioorg Med Chem 22:325-33|
|Chen, Chi-Yuan; Yang, Shuenn-Chen; Lee, Kuo-Hsiung et al. (2014) The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis. J Med Chem 57:677-85|
|Zhao, Xiao-Bo; Goto, Masuo; Song, Zi-Long et al. (2014) Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents. Bioorg Med Chem Lett 24:3850-3|
|Zhang, Zhi-Jun; Tian, Jing; Wang, Li-Ting et al. (2014) Design, synthesis and cytotoxic activity of novel sulfonylurea derivatives of podophyllotoxin. Bioorg Med Chem 22:204-10|
|Wang, Xiao-Feng; Guan, Fang; Ohkoshi, Emika et al. (2014) Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site. J Med Chem 57:1390-402|
|Wang, Yue-Hu; Goto, Masuo; Wang, Li-Ting et al. (2014) Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues. Bioorg Med Chem Lett 24:4818-21|
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