Recent Patents on Anti-Cancer Drug Discovery - Volume 7, Issue 2, 2012

“Biochemistry textbooks present glycolysis and fat synthesis as history, with all of facts known” [1]. However, a new challenge emerges with better understanding of cancer cell metabolism-aerobic glycolysis is approximately 200 times higher in a cancer cell than in the normal cell of origin, even though oxygen is available [2]. Glucose is a universal fuel and building material in organisms due to its low non-specific glycation, a process that often leads to protein damage and dysfunction [3]. Glucose is used for energy (adenosine 5'-triphosphate, ATP) production in cells by aerobic or anaerobic respiration. Through the glycolytic pathway, glucose is also diverted to de novo lipid synthesis (lipogenesis) and other biosynthetic pathways (Fig. (1)). Lipogenesis consists of two processes: long chain fatty acid synthesis and triglyceride synthesis (esterification of fatty acids with glycerol). In cytosol, glucose is glycolyzed into pyruvate that is then converted to citrate in mitochondria. Citrate is transported into the cytosol and cleaved into acetyl-CoA and oxaloacetate by ATP citrate lyase. Cytosolic acetyl-CoA is used for malonyl-CoA formation by acetyl-CoA carboxylases. Fatty acid synthase condensates malonyl-CoA and acetyl-CoA into a long chain fatty acid, saturated palmitate (C16:0) [4, 5]. This de novo fatty acid synthesis from glucose is called a glycolysis-citrate-lipogenesis pathway.....

ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely distributed in various human and animal tissues. ACL links glucose and lipid metabolism by catalyzing the formation of acetyl-CoA and oxaloacetate from citrate produced by glycolysis in the presence of ATP and CoA. ACL is aberrantly expressed in many immortalized cells and tumors, such as breast, liver, colon, lung and prostate cancers, and is correlated reversely with tumor stage and differentiation, serving as a negative prognostic marker. ACL is an upstream enzyme of the long chain fatty acid synthesis, providing acetyl-CoA as an essential component of the fatty acid synthesis. Therefore, ACL is a key enzyme of cellular lipogenesis and potent target for cancer therapy. As a hypolipidemic strategy of metabolic syndrome and cancer treatment, many small chemicals targeting ACL have been designed and developed. This review article provides an update for the research and development of ACL inhibitors with a focus on their patent status, offering a new insight into their potential application.

Acetyl-CoA carboxylases (ACCs) play a rate-limiting role in fatty acid biosynthesis in plants, microbes, mammals and humans. ACCs have the activity of both biotin carboxylase (BC) and carboxyltransferase (CT), catalyzing carboxylation of Acetyl-CoA to malonyl-CoA. In the past years, ACCs have been used as targets for herbicides in agriculture and for drug discovery and development of human diseases, such as microbial infections, diabetes, obesity and cancer. A great number of small molecule ACC inhibitors have been developed, including natural and non-natural (artificial) products. These chemicals target BC reaction, CT reaction or ACC phosphorylation. This article provides a comprehensive review and updates of ACC inhibitors, with a focus on their therapeutic application in metabolic syndromes and malignant diseases. The patent status of common ACC inhibitors is discussed.

Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future.

Fatty acid synthesis is a coordinated process involving multiple enzymes. Overexpression of some of these enzymes plays important roles in tumor growth and development. Therefore, these enzymes are attractive targets for cancer therapies. Antisense agents provide highly specific inhibition of the expression of target genes and thus have served as powerful tools for gene functional studies and potential therapeutic agents for cancers. This article reviews different types of antisense agents and their applications in the modulation of fatty acid synthesis. Patents of antisense agents targeting fatty acid synthetic enzymes are introduced. In addition, miR-122 has been shown to regulate the expression of fatty acid synthetic enzymes, and thus antisense agent patents that inhibit miR-122 expression are also discussed.

Multicellular organisms require apoptosis whereby the human body eliminates unnecessary and/or damaged cells. Apoptosis, or programmed cell death, can indeed be considered as a constitutive anti-cancer mechanism that seems to be defective in more than 50% of cancers. Molecular insights on the biology of the apoptotic process have led to the development of new anti-cancer strategies aiming at recovering and stimulating this process. Preclinical and clinical studies of our and other groups have demonstrated that targeting the extrinsic apoptotic pathway by various death receptors agonists is a safe and effective anti-cancer strategy, which thus may become a new cornerstone of cancer therapy. Here, we review the most recent acquisitions and patents on TRAIL or TRAIL mimetics, as well as the combination therapies that could be used with them.

Discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs derived from the marine environment are continuously developing and increasing. One of the most promising area is cancer therapy. Currently, there are two drugs approved by the Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products (EMA) in cancer treatment, namely Cytarabine (Cytosar-U1®) and Eribulin (E7389 or Halaven®). Trabectedin (ET-743 or Yondelis1®), approved by EMA, is completing key Phase III studies in the U.S. for final approval. It was estimated that 118 marine natural products (MNPs) are currently in preclinical trials, 22 MNPs in clinical trials and 3 MNPs on the market. The characteristics and selectivity profiles of new drugs for cancer therapy, as well as drugs disclosed in related patent applications, will be the focus of this review, providing a brief and ready to use reference.

CRC is the fourth most frequently diagnosed tumor and the second leading cause of cancer death in the United States. KRAS mutations occur in 35-45% of metastatic-CRC and preclude responsiveness to cetuximab or panitumumab. However, less than 20% of KRAS wild-type (wt) patients achieve objective response. Alterations of BRAF/NRAS/ PIK3CA/PTEN, have independently been found to give rise to resistance. The first-line trials with cetuximab chemotherapy are conflicting, because of the many differences among prospective and retrospective evaluations. In neoadjuvant regimens, cetuximab with CT obtained a significant and early increase of the RR. In second-line studies cetuximab improved RR and PFS. In third-line studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Cetuximab has not reported any benefit neither in adjuvant nor in trials with bevacizumab. In thirdline studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Value of KRAS is questioned, since a high percentage of KRAS-wt patients has no benefit with cetuximab. More and more data on the molecular patterns of these tumors underline their biological complexity. Cetuximab treatment is usually well tolerated. Moreover, toxicity seems to correlate with response to treatment. This patents review focuses on recent advances in the treatment of CRC with cetuximab including several novel therapeutic protocols of intervention.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to anti-cancer drug discovery.