Project 3 comprises a collaborative effort between the University of North Carolina at Greensboro (chemistry via the Nicholas Oberlies Lab), Mycosynthetix, Inc. (mycology), and Columbia University (biological evaluation via the Brent Stockwell Lab). It is hypothesized that anticancer drug leads with novel structures will be obtained from filamentous fungi. Hence, the goal of Project 3 is the discovery of structurally diverse and biologically active compounds on a scale that facilitates drug development. To do so, the three specific aims can be summarized as:
Specific Aim 1 : Select and culture fungi from the Mycosynthetix library, focusing on unusual cultures and those likely to produce promising leads.
Specific Aim 2. Dereplication, Isolation and structure elucidation of bioactive lead compounds.
Specific Aim 3. Test samples for oncogenic-Ras selective lethality and novel cell death mechanisms using engineered tumor cells. Project 3 has been revised per the helpful suggestions of the reviewers of the initial application. The three aims for Project 3 work in an iterative manner toward anticancer leads, with unique skills in mycology (Aim 1) providing samples for natural products chemistry (Aim 2) that are evaluated for biological activity (Aim 3). Importantly, this latter aim will focus on compounds that are synthetic lethal with oncogenic Ras. The Ras oncoproteins (K-Ras, H-Ras, N-Ras) are of paramount importance in cancer biology. They were discovered over 30 years ago, but have been resistant to direct targeting with small molecules. Thus, despite the fact that the KRAS gene is mutated in ~20% of all tumors, and >95% of pancreatic cancers, there is no therapy for treating mutant KRAS tumors. Compounds that show increased potency and lethality in tumor cells with oncogenic Ras are likely to exhibit an increased therapeutic index, and to reveal mechanisms for targeting tumors harboring mutations in the three Ras genes (HRAS, NRAS and KRAS). The resources of the Program will be utilized for pushing the best leads towards preclinical development. Besides the skills of the other Projects and Cores, this will include close interaction with our corporate partner, Eisai Inc (Andover, MA), who has a successful track record of developing anticancer natural products. The primary purpose of this part of the program project is to discover new cancer chemotherapeutic agents from cultures of filamentous fungi. In order to do this, our group will perform chemical and biological studies in a coordinated manner with the other components of this project.
|Amrine, Chiraz Soumia M; Raja, Huzefa A; Darveaux, Blaise A et al. (2018) Media studies to enhance the production of verticillins facilitated by in situ chemical analysis. J Ind Microbiol Biotechnol 45:1053-1065|
|Young, Alexandria N; Herrera, Denisse; Huntsman, Andrew C et al. (2018) Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition. Mol Cancer Ther 17:2123-2135|
|Acuña, Ulyana Muñoz; Mo, Shunyan; Zi, Jiachen et al. (2018) Hapalindole H Induces Apoptosis as an Inhibitor of NF-?B and Affects the Intrinsic Mitochondrial Pathway in PC-3 Androgen-insensitive Prostate Cancer Cells. Anticancer Res 38:3299-3307|
|Al-Huniti, Mohammed H; Rivera-Chávez, José; Colón, Katsuya L et al. (2018) Development and Utilization of a Palladium-Catalyzed Dehydration of Primary Amides To Form Nitriles. Org Lett 20:6046-6050|
|Crnkovic, Camila M; Krunic, Aleksej; May, Daniel S et al. (2018) Calothrixamides A and B from the Cultured Cyanobacterium Calothrix sp. UIC 10520. J Nat Prod 81:2083-2090|
|Wilson, Tyler A; Tokarski 2nd, Robert J; Sullivan, Peter et al. (2018) Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin. J Nat Prod 81:534-542|
|Lu, Chunwan; Yang, Dafeng; Sabbatini, Maria E et al. (2018) Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells. BMC Cancer 18:149|
|El-Elimat, Tamam; Rivera-Chávez, José; Burdette, Joanna E et al. (2018) Cytotoxic homoisoflavonoids from the bulbs of Bellevalia flexuosa. Fitoterapia 127:201-206|
|Ren, Yulin; Anaya-Eugenio, Gerardo D; Czarnecki, Austin A et al. (2018) Cytotoxic and NF-?B and mitochondrial transmembrane potential inhibitory pentacyclic triterpenoids from Syzygium corticosum and their semi-synthetic derivatives. Bioorg Med Chem 26:4452-4460|
|Crnkovic, Camila M; May, Daniel S; Orjala, Jimmy (2018) The impact of culture conditions on growth and metabolomic profiles of freshwater cyanobacteria. J Appl Phycol 30:375-384|
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