Trends in the Exploration of Anticancer Targets and Strategies in Enhancing the Efficacy of Drug Targeting
Department of Pharmacy, National University of Singapore, Singapore. Current Molecular Pharmacology
11/2008; 1(3):213-32. DOI: 10.2174/1874-470210801030213
A number of therapeutic targets have been explored for developing anticancer drugs. Continuous efforts have been directed at the discovery of new targets as well as the improvement of therapeutic efficacy of agents directed at explored targets. There are 84 and 488 targets of marketed and investigational drugs for the treatment of cancer or cancer related illness. Analysis of these targets, particularly those of drugs in clinical trials and US patents, provides useful information and perspectives about the trends, strategies and progresses in targeting key cancer-related processes and in overcoming the difficulties in developing efficacious drugs against these targets. The efficacy of anticancer drugs directed at these targets is frequently compromised by counteractive molecular interactions and network crosstalk, negative and adverse secondary effects of drugs, and undesired ADMET profiles. Multi-component therapies directed at multiple targets and improved drug targeting methods are being explored for alleviating these efficacy-reducing processes. Investigation of the modes of actions of these combinations and targeting methods offers clues to aid the development of more effective anticancer therapies.
Available from: Christopher H Switzer
- "Even with this success, the clinical reality is that cancer persists, and even recurs within the same patient, due to tumor heterogeneity, which leads to an attenuated response to an individual anti-cancer therapy. Thus it is necessary to develop agents that do not target just one pathway, but instead, concurrently target several cancer pathways without toxicity toward healthy tissues (Zhu et al., 2008). COG112 showed selective proliferation inhibition for aggressive cancer cells but did not affect normal fibroblasts (Figure 3E), suggesting that COG112 may fulfill these ideal requirements. "
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ABSTRACT: The SET oncoprotein participates in cancer progression by affecting multiple cellular processes, inhibiting the tumor suppressor protein phosphatase 2A (PP2A), and inhibiting the metastasis suppressor nm23-H1. On the basis of these multiple activities, we hypothesized that targeted inhibition of SET would have multiple discrete and measurable effects on cancer cells. Here, the effects of inhibiting SET oncoprotein function on intracellular signaling and proliferation of human cancer cell lines was investigated. We observed the effects of COG112, a novel SET interacting peptide, on PP2A activity, Akt signaling, nm23-H1 activity and cellular migration/invasion in human U87 glioblastoma and MDA-MB-231 breast adenocarcinoma cancer cell lines. We found that COG112 interacted with SET protein and inhibited the association between SET and PP2A catalytic subunit (PP2A-c) and nm23-H1. The interaction between COG112 and SET caused PP2A phosphatase and nm23-H1 exonuclease activities to increase. COG112-mediated increases in PP2A activity resulted in the inhibition of Akt signaling and cellular proliferation. Additionally, COG112 inhibited SET association with Ras-related C(3) botulinum toxin substrate 1 (Rac1), leading to decreased cellular migration and invasion. COG112 treatment releases the SET-mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1. These results establish SET as a novel molecular target and that the inhibition of SET may have beneficial effects in cancer chemotherapy.
Oncogene 02/2011; 30(22):2504-13. DOI:10.1038/onc.2010.622 · 8.46 Impact Factor
Available from: Carmen Plasencia
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ABSTRACT: Previously, we discovered a novel class of salicylhydrazide compounds with remarkable activity in hormone-dependent and -independent human cancer cells. We then designed and synthesized numerous analogues. Among these analogues, a quinoxalinhydrazide compound, SC144, exhibited desirable physicochemical and drug-like properties and therefore was selected for further preclinical investigation. In the present study, we evaluated the in vitro activity of SC144 in a range of drug-sensitive and -resistant cancer cell lines as well as its in vivo efficacy in MDA-MB-435 and HT29 mice xenograft models. The broad-spectrum cytotoxicity of SC144 is especially highlighted by its potency in ovarian cancer cells resistant to cisplatin, breast-cancer cells resistant to doxorubicin, and colon cancer cells resistant to oxaliplatin. Furthermore, its activity was independent of p53, HER-2, estrogen and androgen receptor expressions. We also examined the effect of SC144 on cell cycle progression and apoptosis in select cell lines. Considering its cytotoxicity profile in a variety of in vitro and in vivo cancer models as well as its effects on cell cycle regulation and apoptosis, SC144 appears to represent a promising agent for further clinical development.
Cancer biology & therapy 04/2009; 8(5):458-65. DOI:10.4161/cbt.8.5.7741 · 3.07 Impact Factor
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ABSTRACT: Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets. A challenge in drug discovery is to decide which targets to pursue from an increasing pool of potential targets, given the fact that few innovative targets have made it to the approval list each year. Knowledge of existing drug targets (both approved and within clinical trials) is highly useful for facilitating target discovery, selection, exploration and tool development. The Therapeutic Target Database (TTD) has been developed and updated to provide information on 358 successful targets, 251 clinical trial targets and 1254 research targets in addition to 1511 approved drugs, 1118 clinical trials drugs and 2331 experimental drugs linked to their primary targets (3257 drugs with available structure data). This review briefly describes the TTD database and illustrates how its data can be explored for facilitating target and drug searches, the study of the mechanism of multi-target drugs and the development of in silico target discovery tools.
Expert Opinion on Therapeutic Targets 05/2011; 15(8):903-12. DOI:10.1517/14728222.2011.586635 · 5.14 Impact Factor
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