Current Topics in Medicinal Chemistry - Volume 8, Issue 10, 2008

In 1971 President Richard Nixon declared a “War on Cancer” and requested an allocation of 100 million dollars from the US Congress to find a cure. In spite of the vast research efforts since then, the American Cancer Society estimates that in the United States 565,650 people will die from cancer this year and 1,437,000 new cancers will be diagnosed. The picture worldwide is similarly gloomy with an estimated 7.6 million cancer deaths and 12 million new cases for 2007. Therefore, although there are almost 200 drugs currently approved for the treatment of cancer, there remains a large unmet need for new therapeutic agents. This special issue of Current Topics in Medicinal Chemistry is devoted to the review of some exciting new oncology targets and the progress that has been made on identifying small molecule inhibitors of these targets. The issue begins with an overview of potential anti-cancer therapeutics that can inhibit some key proteins that control the activity of numerous signaling pathways implicated in tumor development. In the first article, Moradei and coworkers at MethylGene discuss inhibitors of histone deacetylase (HDAC), enzymes whose inhibition results in cell cycle arrest or apoptosis in cancer cells. The second article by Drysdale and Brough of Vernalis focuses on new inhibitors of heat shock protein 90 (HSP90), a molecular chaperone whose function is to stabilize cellular proteins, many of which are oncogenes. The next two reviews describe inhibitors of targets with less pleiotropic but nonetheless profound effects on tumor cells. The first is an update on nonsteroidal aromatase inhibitors for the treatment of hormone-dependent breast cancer by Gobbi and coworkers at the University of Bologna, who also discuss some new multi-targeted compounds. This paper is followed by a discussion from Knight and Parrish of GlaxoSmithKline on inhibitors of the mitotic kinesin spindle protein (KSP), an intracellular motor protein whose inhibition results in mitotic arrest. Imatinib, being the first small molecule kinase inhibitor to reach the market, was the poster child of oncology drug discovery in the last decade. Imatinib inhibits the activity of Abl kinase, and the presence of an activated form of this kinase is the hallmark of chronic myelogenous leukemia (CML). Imatinib is highly efficacious in treating early stage CML patients but resistance to the drug can occur, often as the result of mutations in the kinase domain of Abl. In the penultimate review, Noronha and coworkers at TargeGen describe efforts to develop new Abl inhibitors including those that can also inhibit the most clinically refractory mutation, that of threonine 315 to isoleucine. In the final article which focuses on a single class of Src kinase inhibitors, the 3-quinolinecarbonitriles, I describe how optimization of this series by Wyeth resulted in a dual inhibitor of both Src and Abl kinases that is currently in clinical trials for the treatment of CML. Many thanks to all the authors for their comprehensive contributions and to Allen Reitz for the invitation to serve as the Guest Editor for this issue. Our aim was to present a cross section of the different approaches being used to combat cancer and we hope that readers will find this issue to be informative and perhaps even inspiring. The ultimate goal however remains winning the war.

Histone deacetylase (HDAC) inhibitors constitute a novel and growing class of anticancer agents that function by altering intracellular patterns of histone acetylation, the so-called epigenetic “histone code,” thereby producing changes in cell cycle arrest, differentiation, and/or apoptosis in tumor cells. This overview describes the chemistry and preliminary characterization of recently disclosed molecules in three major classes of HDAC inhibitors: hydroxamic acids, 2-aminobenzanilides, and cyclic peptides. In addition, results from recent clinical trials on isotype-selective HDAC inhibitors are reviewed. It is clear from the plethora of new molecules and the encouraging results from clinical trials that HDAC inhibitors hold a great deal of promise, particularly as add-on therapy, for the treatment of a variety of solid and hematologic cancers.

Heat shock protein (Hsp90) inhibitors are an increasingly interesting and important class of compounds where the first in class, natural product derived inhibitors such as 17-allylaminogeldanamycin (17-AAG), are entering late stage clinical development. Recently the emergence of synthetic, small molecule inhibitors has been described and both NVPAUY922 and BIIB021 have entered clinical development. The medicinal chemistry of these and other published small molecule Hsp90 inhibitors is described in this review.

Aromatase is the enzyme responsible for the conversion of androgens to estrogens and represents the main source of local estrogens in post-menopausal breast cancer tissue. Nonsteroidal aromatase inhibitors (NSAIs) are able to reduce growth-stimulatory effects of estrogens in hormone-dependent breast cancer, and third generation NSAIs are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic advanced breast cancer. Nevertheless, some issues in this area still need to be addressed and research efforts are aimed both at identifying new molecules of therapeutic interest and at exploring different options for the modulation of this enzyme. In this review, an update of the latest developments in the field of NSAIs is presented, to provide a broad view on the recent progress in this area. Beside classical structure-activity relationships studies and development of natural product derivatives, rational approaches for both ligand- and structure-based design are described. Moreover, novel strategies for the development of multitarget-directed molecules are also presented. Finally, some possible future developments in this research area are briefly considered.

Kinesin spindle protein (KSP), a mitotic kinesin responsible for bipolar spindle establishment and maintenance, is currently the target of intense research for the development of novel anticancer therapeutics. Several inhibitors of KSP have progressed into clinical trials and many others are in preclinical development. A majority of these inhibitors are ATP-uncompetitive and bind in an allosteric loop L5 binding pocket, but recently, inhibitors with an alternative mechanism of action (ATP-competitive) have also been identified and characterized. In this review, an update of the clinical trial results with ATP-uncompetitive KSP inhibitors is provided and recent progress in the identification of additional KSP inhibitors is discussed.

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2nd generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2nd generation inhibitors with the exception of the T315I mutant. Several 3rd generation inhibitors such as AP24534, VX-680 (MK-0457), PHA- 739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.

In 2000, Wyeth reported that the 3-quinolinecarbonitrile ring system was a template for EGFR inhibitors. It soon became apparent that the group at C-4 of this core was responsible for kinase selectivity. A 4-(2,4-dichloro-5- methoxyanilino) substituent provided potent inhibitors of Src, a non-receptor tyrosine kinase that plays a key role in cell signaling. One compound from this series, SKI-606, bosutinib, is currently in clinical trials for the treatment of cancer.

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