Discovery of Novel Cytotoxic Agents for Advanced Melanoma

Summary

Principal Investigator: Wei Li
Abstract: [unreadable] DESCRIPTION (provided by applicant): Discovery of Novel Cytotoxic Agents for Advanced Melanoma While melanoma in early stages can usually be cured by surgical removal, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of research, Dacarbazine (DTIC) still remains the only FDA approved drug to treat advanced melanoma, yet it only provides complete remission in less than 5% of patients. With the rapidly rising incidents of melanoma in the United States, there is an urgent need to develop novel chemotherapeutic agents for this disease. We recently identified three potent lead compounds against melanoma in vitro. Unlike DTIC, these molecules are not alkylation agents. Most likely they interfere with growth factors and other molecules involved in the cancer cell's signaling pathways. The most potent lead compounds have IC50 values in the sub-micromole range with over 10 fold selectivity against cancer cells. Compared with the drug Sorafenib which showed promising effects for melanoma treatment in clinical trials, these novel compounds are more potent and more selective. The mechanisms of action of these compounds are likely to be different from existing anticancer drugs such as DTIC, Taxol, or Sorafenib. In this proposal, we plan to perform extensive synthesis and SAR studies to further optimize the potency and selectivity of these compounds. Our central hypothesis is that new analogs of our lead structures could achieve better selectivity than existing drugs used in clinical trials, while possessing much higher potency towards melanoma. Our specific aims are: (1) to synthesize focused sets of thiazolidine analogs, followed by extensive structure activity relationships (SAR) studies for lead optimization; (2) parallel to the synthetic efforts and biological testing, to use combinations of analytical techniques in both biology and chemistry to investigate the possible mechanisms of action and verify the drug targets for these novel compounds. High resolution magic angle spinning NMR (HR-MAS NMR) and other advanced analytical techniques will be used for global analysis of adaptive metabolic responses in an analogous fashion to genomics and proteomics experiments. The ultimate goal for this project is to synthesize and identify sets of the most promising compounds having novel mechanisms of actions for further in vivo development. PUBLIC HEALTH RELEVANCE: There is currently no curative therapy for advanced melanoma; available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to synthesize novel classes of compounds as potential therapeutic agents. Studies proposed herein are designed to test the hypothesis that the activity of these compounds will have improved efficacy and can be optimized and provide the groundwork for the development of a new class of therapeutic agents to treat advanced aggressive melanoma. This is a high risk, innovative proposal to discover a non-surgical means for a more selective and curative pharmacologic therapy for advanced melanoma. [unreadable] [unreadable] [unreadable]
Funding Period: 2008-03-05 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Synthesis and antiproliferative activity of imidazole and imidazoline analogs for melanoma
    Jianjun Chen
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Bioorg Med Chem Lett 18:3183-7. 2008
  2. pmc Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor
    Chien Ming Li
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
    Cancer Res 71:216-24. 2011
  3. pmc 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells
    Andrzej T Slominski
    Dept of Pathology and Laboratory Medicine, Center for Cancer Research, Univ of Tennessee Health Science Center, 930 Madison Ave, RM525, Memphis, TN 38163, USA
    Am J Physiol Cell Physiol 300:C526-41. 2011
  4. ncbi Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, United States
    J Med Chem 54:4678-93. 2011
  5. pmc Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents
    Jianjun Chen
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
    J Med Chem 53:7414-27. 2010
  6. pmc A new steroidal 5,7-diene derivative, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid, shows potent anti-proliferative activity
    Tae Kang Kim
    Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Steroids 75:230-9. 2010
  7. pmc Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity
    Wei Li
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Steroids 75:926-35. 2010
  8. ncbi Synthesis, in vitro structure-activity relationship, and in vivo studies of 2-arylthiazolidine-4-carboxylic acid amides as anticancer agents
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States
    Bioorg Med Chem 18:477-95. 2010
  9. pmc High-resolution magic angle spinning nuclear magnetic resonance analysis of metabolic changes in melanoma cells after induction of melanogenesis
    Wei Li
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Anal Biochem 386:282-4. 2009
  10. pmc Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA
    J Med Chem 52:1701-11. 2009

Detail Information

Publications13

  1. pmc Synthesis and antiproliferative activity of imidazole and imidazoline analogs for melanoma
    Jianjun Chen
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Bioorg Med Chem Lett 18:3183-7. 2008
    ..These structure-activity studies indicated that the thiazolidine ring is very critical for the activity for these series of compounds...
  2. pmc Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor
    Chien Ming Li
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
    Cancer Res 71:216-24. 2011
    ....
  3. pmc 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells
    Andrzej T Slominski
    Dept of Pathology and Laboratory Medicine, Center for Cancer Research, Univ of Tennessee Health Science Center, 930 Madison Ave, RM525, Memphis, TN 38163, USA
    Am J Physiol Cell Physiol 300:C526-41. 2011
    ..Thus 20(OH)D(2) shows cell-type dependent antiproliferative and prodifferentiation activities through activation of VDR, while having no detectable toxic calcemic activity, and is a poor substrate for CYP27B1...
  4. ncbi Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, United States
    J Med Chem 54:4678-93. 2011
    ....
  5. pmc Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents
    Jianjun Chen
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
    J Med Chem 53:7414-27. 2010
    ..In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors...
  6. pmc A new steroidal 5,7-diene derivative, 3beta-hydroxyandrosta-5,7-diene-17beta-carboxylic acid, shows potent anti-proliferative activity
    Tae Kang Kim
    Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Steroids 75:230-9. 2010
    ....
  7. pmc Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity
    Wei Li
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Steroids 75:926-35. 2010
    ....
  8. ncbi Synthesis, in vitro structure-activity relationship, and in vivo studies of 2-arylthiazolidine-4-carboxylic acid amides as anticancer agents
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States
    Bioorg Med Chem 18:477-95. 2010
    ..At a dose of 10mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60mg/kg...
  9. pmc High-resolution magic angle spinning nuclear magnetic resonance analysis of metabolic changes in melanoma cells after induction of melanogenesis
    Wei Li
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Anal Biochem 386:282-4. 2009
    ....
  10. pmc Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships
    Yan Lu
    Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA
    J Med Chem 52:1701-11. 2009
    ..Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization...
  11. pmc Identifying novel molecular structures for advanced melanoma by ligand-based virtual screening
    Zhao Wang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    J Chem Inf Model 49:1420-7. 2009
    ..One of the newly synthesized analogs based on this virtual screening has improved potency and selectivity against melanoma...
  12. pmc Sequential metabolism of 7-dehydrocholesterol to steroidal 5,7-dienes in adrenal glands and its biological implication in the skin
    Andrzej T Slominski
    Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
    PLoS ONE 4:e4309. 2009
    ..The 5-7 dienal intermediates of the pathway can be a source of biologically active vitamin D3 derivatives after delivery to or production in the skin, an organ intermittently exposed to solar radiation...
  13. pmc Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity
    Michal A Zmijewski
    Department of Histology, Medical University of Gdansk, Gdansk, Poland
    Steroids 76:193-203. 2011
    ..In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells...