Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 5, Number 12, 2005

Contents

New Approaches to Treating Cancer: Medicinal Chemistry and Therapeutic Potential
Guest Editor: David J. Weber


Editorial Pp.1091


Design of Inhibitors for S100B Pp.1093
Joseph Markowitz, Alexander D. MacKerell Jr., France Carrier, Thomas H. Charpentier and David J. Weber
[Abstract]


Cell Cycle Regulatory Kinase Modulators: Interim Progress and Issues Pp.1109
Edward A. Sausville
[Abstract]


Peptide Nucleic Acid Conjugates: Synthesis, Properties and Applications Pp.1119
Zhanna V. Zhilina, Amy J. Ziemba, and Scot W. Ebbinghaus
[Abstract]


DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents Pp.1133
Klaus Pors and Laurence H. Patterson
[Abstract]


Combining Cytotoxic and Immune-Mediated Gene Therapy
to Treat Brain Tumors Pp.1151
James F. Curtin, Gwendalyn D. King, Marianela Candolfi, Remy B. Greeno, Kurt M. Kroeger, Pedro R. Lowenstein and Maria G. Castro
[Abstract]


Carbohydrate Mimotopes in the Rational Design of Cancer Vaccines Pp.1171
Anastas Pashov, Marty Perry, Michael Dyar, Marie Chow and Thomas Kieber-Emmons
[Abstract]




Abstracts

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Editorial

New Approaches to Treating Cancer: Medicinal Chemistry and Therapeutic Potential

Leaders from the drug industry, academic medicine, the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) report that since 1993 the money spent on drug development is rising, while submissions to the FDA for treatments of disease are steadily decreasing. Numerous explanations for this problem were presented in this joint report from the Association of American Medical Colleges (AAMC) and the Food and Drug Administration (FDA) entitled “Drug Development Science: Obstacles and Opportunities for Collaboration among Academia, Industry, and Government” (edited by Drs. David Korn and Donald Stanski). It was also clear that the AAMC/FDA panel agreed that the pharmaceutical industry alone cannot reverse this downward trend and that immediate collaboration between pharmaceutical companies, government agencies (i.e. NIH, DOD, etc) and academic research is absolutely necessary for the timely discovery and development of new and effective therapies. One of the immediate opportunities for collaboration identified in this report is to “translate the basic science explosion into validated drug targets”. Such collaboration should include identifying and validating potential targets and understanding the biology of such targets both in cancer patients as well as in healthy individuals. Such research is critically important for the identification of reasonable targets and appropriate therapeutic strategies early in the process. Also recognized as important, is the continued development of state-of-the-art methodologies for use in drug-design programs and/or for optimizing therapeutic treatments.

In this issue of Current Topics in Medicinal Chemistry entitled “New Approaches to Treating Cancer: Medicinal Chemistry and Therapeutic Potential”, seven reviews address several new drug targets, new methodologies, and biological implications of existing and potential therapies. Specifically, in a paper from my group, we discuss the identification of a new therapeutic target, S100B, which has long been recognized as a marker for malignant melanoma and gliomas. Our group has recently discovered that S100B is not just a marker, but rather it contributes to cellular proliferation in these and other cancers by down-regulating wild-type p53. An approach for discovering lead compounds that inhibit the S100B-p53 interaction and restores wild-type p53 tumor suppressor activity is discussed. Also included are state-of-the-art methodologies including computational techniques, structural biology techniques, and cellular assays.

In a review by Dr. Edward Sausville, the progress of developing cell cycle regulatory kinase modulators such as flavopiridol, seliciclib, and UCN-01 is presented. These results together with structural data has allowed the refinement of screening strategies directed at cell cycle regulatory kinases, including cdks, chk kinases, and some most recent targets, the mitotic phase aurora kinases. In addition, other mechanisms of action for flavopiridol and seliciclib (i.e. as modulators of gene expression) were discussed as were the development of new CDK inhibitors and other modulators of the cell cycle. The clinical implications of using such drugs in combination with other therapies were also covered. In recent discussions of these topics with Dr. Sausville, he points out that “among the challenges faced by academics who actually define a novel mechanism from treatment with a particular compound is that the path to regulatory approval is not always clear.” For example, Flavopiridol started its existence as a cyclin dependent kinase inhibitor. Numerous clinical studies were undertaken before it was appreciated that this target actually also governed transcription, and that additional strategies that target rapidly turning over gene sets might be an additional and perhaps a superior strategy. Such results have prompted Dr. Sausville to recommend that a mechanism be put in place that allows the inclusion of feedback from early trials and new biological results in the drug development process, an idea echoed in the AAMC/FDA report.

Another topic addressed in this CTMC issue is the problem of chemo-resistance. In a review by Pors and Patterson, the role of DNA mismatch repair (MMR) in cancers (i.e. leukemia, colon, gastric, breast, ovarian, prostrate, etc) that are resistant to numerous forms of chemotherapy is discussed as well as how to begin combating this problem. For example, in some chemo-resistant cancer cells, agents such as decitabine are designed to restore functional MMR by inhibiting the hypermethylation of the promoter for hMLH1, which is a component of the hMutS?/hMutL? MMR machinery. On the other hand, if MMR is deficient due to gene mutation, such a strategy is not effective. Yet cells such as these are sometimes hypersensitive to agents such as mitomycin C, camptothecin, or novel hydroxyethylaminoanthraquinones, which provides an alternative therapeutic advantage for treatment of chemo-resistant cancers.

In addition to small molecule inhibitor design, other approaches for treating cancers are also considered in this issue of CTMC. For example, the use of peptide-nucleic acid conjugates (PNAs) for silencing gene expression is an approach for regulating/treating disease states. However, the intracellular delivery of such compounds is problematic, and requires conjugation of PNAs with lipophilic moieties, peptides, and other molecules for delivery. Such modifications and other designs of PNA molecules (i.e. fluorescent, photoreactive, intercalators, alkylators, etc) for use in targeting and/or studying gene expression is the topic of a review by Scot Ebbinghaus and colleagues. Maria Castro and colleagues examine existing and potential treatments for glioblastoma (GBM), a cancer for which there is currently no cure. The emphasis in this manuscript is on advances made using immunotherapeutic strategies including the use of gene therapy, various combination therapies, and novel approaches with various targeted toxin constructs. The incorporation of in vivo imaging techniques, such as magnetic resonance imaging (MRI), positron emission tomography (PET) and bioluminescence imaging, as tools to monitor therapeutic efficacy in such treatments is also incorporated into this paper. In a review by Dr. Kieber-Emmons, such structural requirements and approaches for vaccine design that rely on peptide mimics of tumor associated carbohydrate antigens (TACA) are examined. A unique advantage with peptide “mimotopes” of TACA is that it combines the beneficial properties of peptide antigens with the fact that multiple proteins and lipids on cancer cells are often modified with the same carbohydrate structure, which lowers the risk of developing resistant tumors due to the loss of any one antigen.

While there are very large hurdles and many paths for drug discovery, there are several outstanding success stories where an NIH-funded academic principal investigator takes an idea from their basic research laboratory all the way to the patients’ bedside. From my own institution, Angela Brody, Ph.D. together with the Pharmaceutical Company Novartis developed several aromatase inhibitors including Formestane (4-hydroxyandrostenedione) and Letrozole that are now the new standard care for the treatment of breast cancer in postmenopausal women. Drs. Brian Druker, M.D. and Nicholas Lydon, Ph.D. contributed significantly to the development of GleevacTM (Imatinib mesylate), a prescribed tyrosine kinase inhibitor used for the treatment of patients with chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), and other cancers. Another example is the use of a new polymer based system for the delivery of existing pharmaceuticals to patients with brain or prostate cancer that was developed by Dr. Robert Langer, Sc.D., a Professor of Chemical and Biochemical Engineering at the Massachusetts Institute of Technology. Dr. Langer’s discovery has led to improving treatments by reducing side effects and by providing better chemotherapeutic regimes. These and numerous other PIs who have had similar successes should be taken as inspirations to all of us in academic medicine to continue examining potential drug targets and therapeutic strategies. A goal of such work should be to eventually partner with government agencies and/or drug companies, as was done by the PIs mentioned here and as recommended by the AAMC/FDA report, to take such discoveries to the next step of therapeutic development, so the public can benefit in a timelier manner.

D.J. Weber
The University of Maryland School of Medicine
Department of Biochemistry & Molecular Biology
Baltimore, MD, 21201,
USA


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Design of Inhibitors for S100B
Joseph Markowitz, Alexander D. MacKerell Jr., France Carrier, Thomas H. Charpentier and David J. Weber

S100B interacts with the p53 protein in a calcium-dependent manner and down-regulates its function as a tumor suppressor. Therefore, inhibiting the S100B-p53 interaction represents a new approach for restoring functional wild-type p53 in cancers with elevated S100B such as found in malignant melanoma. A discussion of the biological rational for targeting S100B and a description of methodologies relevant to the discovery of compounds that inhibit S100B-p53 binding, including computational techniques, structural biology techniques, and cellular assays, is presented.


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Cell Cycle Regulatory Kinase Modulators: Interim Progress and Issues
Edward A. Sausville

Since a prior review of cell cycle inhibitors developed at the National Cancer Institute, (Sausville E.A.; Curr Med Chem –Anti Cancer Agents 2003, 3, 47) continued progress in the application of these molecules has been pursued. Evidence of preliminary activity on the part of flavopiridol in certain chronic leukemias has pointed to that disease area as of potential interest, but likely by affecting transcriptional regulation through non-cell cycle-related CDKs. Brief duration infusion early phase trials with UCN-01, and combination studies with cytotoxics are commencing. Emerging structural data has refined the basis for screening strategies directed at cell cycle regulatory kinases, including cdks, chk kinases and most recently the mitotic phase aurora kinases. This interval progress report will review and update progress in these related but distinct drug discovery and development interest areas.


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Peptide Nucleic Acid Conjugates: Synthesis, Properties and Applications
Zhanna V. Zhilina, Amy J. Ziemba, and Scot W. Ebbinghaus

Artificial control of gene expression has great potential in the treatment of many human diseases, and peptide nucleic acids (PNAs) offer several potential advantages for silencing gene expression in mammalian cells. The pseudopeptide backbone of the PNA makes it resistant to enzymatic degradation, and PNAs bind complementary DNA and RNA with high affinity and specificity. PNAs are potentially leading agents for antigene and antisense therapeutics, but the application of PNAs in the in vivo setting is hampered by their poor intracellular delivery. This problem has been addressed by PNA conjugation to lipophilic moieties, peptides, and cell-specific receptor ligands. The biological activity of PNAs can also benefit from conjugation to DNA interactive compounds like intercalators and alkylators. Here we review the most interesting literature concerning PNA conjugation with small molecules, emphasizing synthetic approaches, properties and applications of the PNA conjugates.


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DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents
Klaus Pors and Laurence H. Patterson

DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.


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Combining Cytotoxic and Immune-Mediated Gene Therapy
to Treat Brain Tumors
James F. Curtin, Gwendalyn D. King, Marianela Candolfi, Remy B. Greeno, Kurt M. Kroeger, Pedro R. Lowenstein and Maria G. Castro

In psychiatry, particularly in antidepressant clinical studies, placebo-controlled trials often yield results that are very difficult to interpret because of robust placebo responses. Meta-analyses of trials in major depressive disorder (MDD) suggest that drug-placebo differences in response rates range from 11% to 18%. However, in trials of marketed antidepressants present in the FDA databases, antidepressant drugs were superior to placebo in only 45 out of 93 RCTs (48%), and the placebo response overall appears to have increased over time. This gradual increase in placebo response rates may lead to delays in bringing new antidepressant treatments to the market, increased costs of antidepressant drug development and, in some cases, decisions to stop the development of certain compounds, or FDA decisions to not approve new treatments. A number of possible contributing factors to this significant placebo response in MDD have been identified, but further studies are needed. Many of the remedies used by researchers to minimize the placebo response, such as lead-in periods or shortening the duration of study visits, have failed to show consistent benefits. From our analysis of published studies, it appears that expectations about the speed of response may be shaped by the duration of the trial and that most of the placebo response occurs in the first half of the trial, regardless of its duration. These observations have led us to develop a novel approach to the placebo response problem called the Sequential Parallel Comparison Design.


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Carbohydrate Mimotopes in the Rational Design of Cancer Vaccines
Anastas Pashov, Marty Perry, Michael Dyar, Marie Chow
and Thomas Kieber-Emmons

The task of rationally designing vaccines that can effectively impact on the survival of cancer patients remains challenging. Monoclonal antibodies and T cell receptors have proven to be viable templates for the application of pharmacophore design principles to develop antigens and immunogens as these immune system molecules recognize a variety of sequentially and structurally unrelated ligands. This structural information combined with immunological assessment has contributed to the development of strategies to elicit effective humoral and cellular responses to cancer cells. Understanding the structural requirements for antibody and T cell recognition provides a basis for identifying potentially new sets of immunogens that may have both fundamental immunological and clinical value. Here we review the structural concepts and approaches used in vaccine design applications that illustrate the value and limitations of using chemical (peptide libraries) and immunological information to define novel peptide immunogens that function as mimotopes to generate immune responses targeting tumor associated carbohydrate antigens.