The long-term objective of this proposal is to develop a novel class of anti-cancer agents based on the plant derived compound parthenolide (PTL). Previous studies have demonstrated that PTL has potent cytotoxic activity against a broad range of malignancies, including cancers of the breast, lung, prostate, colon, liver, kidney, pancreas, brain, and bone. In addition to solid tumor studies, several groups including our own have focused on human leukemia (or related hematologic malignancies). We have demonstrated that PTL is highly cytotoxic to primary human leukemia specimens, but non-toxic to normal blood-forming tissues. Thus, the collective evidence suggests that PTL has broad potential as an anti-cancer agent. However, despite the remarkable properties of this compound, clinical development has been very limited, likely due to the poor pharmacological properties of PTL. Indeed, to our knowledge the only PTL-based compound to reach clinical trial stage work is dimethylamino parthenolide (DMAPT), which we previously developed as an orally bioavailable PTL analog. Thus, going forward we believe that applying novel strategies to create more pharmacologically useful forms of PTL-based agents is a high priority. In the course of performing various chemical modifications of PTL, it was demonstrated that the C-10 methyl group can be hydroxylated by reaction with a suitable oxidizing agent. This reaction changes the geometry of the C-9-C-10 double bond from Z to E to afford a hydroxymethyl 1(10)-cis-parthenolide analogue, a compound previously described as melampomagnolide B (MM-B). Intriguingly, the biological activity of MM-B is identical to PTL, retaining strong specificity for leukemia cells. The presence of the C-10 hydroxymethyl group now creates the opportunity for designing an entirely new class of PTL analog. Thus, in the present application we propose to develop and test novel MM-B-based products. Specifically, the aims of the study will be to 1) synthesize novel water-soluble MM-B prodrugs, 2) perform pharmacological and biological efficacy studies, and 3) perform molecular and cellular characterization of the mechanism of action of MM-B. Taken together these studies will create and validate an entirely new type of anti-cancer agent. In addition, by characterizing the molecular mechanism of action of this novel PTL derivative, it should be possible to further refine strategies for the selective eradication of cancer cells.

Public Health Relevance

The goal of this project is to identify new and better ways to treat leukemia. We propose to develop new drugs derived from the naturally occurring compound parthenolide, which has shown significant activity as an anti-leukemia agent. Our studies will synthesize and test novel orally-available parthenolide derivatives

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158275-06
Application #
8857111
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
6
Fiscal Year
2015
Total Cost
$313,325
Indirect Cost
$49,281
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Janganati, Venumadhav; Ponder, Jessica; Balasubramaniam, Meenakshisundaram et al. (2018) MMB triazole analogs are potent NF-?B inhibitors and anti-cancer agents against both hematological and solid tumor cells. Eur J Med Chem 157:562-581
Lamture, Gauri; Crooks, Peter A; Borrelli, Michael J (2018) Actinomycin-D and dimethylamino-parthenolide synergism in treating human pancreatic cancer cells. Drug Dev Res 79:287-294
Albayati, Zaineb A F; Janganati, Venumadhav; Chen, Zheng et al. (2017) Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia. Bioorg Med Chem 25:1235-1241
Janganati, Venumadhav; Ponder, Jessica; Thakkar, Shraddha et al. (2017) Succinamide derivatives of melampomagnolide B and their anti-cancer activities. Bioorg Med Chem 25:3694-3705
Bommagani, Shobanbabu; Ponder, Jessica; Penthala, Narsimha R et al. (2017) Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells. Eur J Med Chem 136:393-405
Mendonca, Marc S; Turchan, William T; Alpuche, Melanie E et al. (2017) DMAPT inhibits NF-?B activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo. Free Radic Biol Med 112:318-326
Penthala, Narsimha Reddy; Janganati, Venumadhav; Alpe, Terri L et al. (2016) N-[11CH3]Dimethylaminoparthenolide (DMAPT) uptake into orthotopic 9LSF glioblastoma tumors in the rat. Bioorg Med Chem Lett 26:5883-5886
Pei, Shanshan; Minhajuddin, Mohammad; D'Alessandro, Angelo et al. (2016) Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells. J Biol Chem 291:21984-22000
Madadi, Nikhil R; Ketkar, Amit; Penthala, Narsimha R et al. (2016) Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells. Bioorg Med Chem Lett 26:2164-9
Sau, Andrea; Lau, Rosanna; Cabrita, Miguel A et al. (2016) Persistent Activation of NF-?B in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage. Cell Stem Cell 19:52-65

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