Current Topics in Medicinal Chemistry - Volume 5, Issue 2, 2005

Cancer continues to be the second leading cause of death in developed countries despite monumental basic research and clinical efforts waged by both government and industry. Although it is clear that we are continuing to refine our understanding of mechanisms for malignant transformation, growth, and resistance of cancers, so it is also evident that we have a significantly difficult path ahead. Multiple, inter-related and redund Read More

This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major ca Read More

Kinesins, mechanochemical enzymes that utilize the energy of ATP to translocate along or destabilize microtubules, are essential for accurate completion of cell division. Recently, small moleculer inhibitors of one kinesin, kinesin spindle protein (KSP/Eg5/kinesin5), have been shown to be efficacious in pre-clinical studies, with one quinazolinone-based inhibitor advancing to Phase II clinical trials as a potential anticancer che Read More

The Hedgehog (Hh) signaling pathway directs the development of multiple tissues during embryonic development, and contributes to tissue homeostasis in adults. Deficient Hh signaling results in defective embryogenesis; conversely, excessive Hh signaling is associated with an inherited cancer predisposition syndrome (Gorlin Syndrome), and a growing list of sporadic human cancers. It is now clear that multiple compone Read More

The discovery of the key negative regulator MDM2 (mouse double minute 2, also termed HDM2 for its human equivalent) provided a great opportunity to manipulate the levels of the tumor suppressor p53 in cancer cells. Activation of p53 in tumor cells by inhibiting the interaction of MDM2 with p53 has therefore been the focus of a large effort in drug discovery. The modulation of protein-protein interactions, however Read More

Loss of normal cell cycle regulation is the hallmark of human cancers, and alteration of the components involved in cell cycle regulation occurs in most human tumors. This suggests that Cyclin dependent kinases (CDKs) are an attractive target for the development of pharmacological agents for the treatment of cancer. Recently, CDK family members that are not directly involved in cell cycle regulation have been identified. T Read More

Polo-like kinases (PLKs) are key enzymes that control mitotic entry of proliferating cells and regulate many aspects of mitosis necessary for successful cytokinesis. Of the four known human PLKs, PLK1 is the best characterized and is overexpressed in many tumour types with aberrant elevation frequently constituting a prognostic indicator of poor disease outcome. Despite the fact that PLK1 has been regarded as a vali Read More

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anticancer agents. The Aurora kinases represent one such family of mitotic regulat Read More

This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant mela Read More