Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics

Abstract

A major goal of cancer research is to translate our understanding of the causation of malignancy at the level of the genome and biochemical pathways into the development of drugs with improved activity and cancer selectivity. This paper provides a personal perspective of the current status of efforts to achieve this goal, with a particular focus on drugging the cancer kinome. Remarkable progress has been made in this area, but many challenges remain. The value of cancer kinome sequencing is emphasized. Three projects in which the author's laboratory is involved are reviewed in detail. These involve the discovery and development of inhibitors of cyclin-dependent kinases, phosphoinositide 3-kinases, and the Hsp90 molecular chaperone.ples from our own recent experience in developing smallmolecule inhibitors against three molecular targets, namely cyclin-dependent kinases (CDKs), phosphoinositide 3-kinase (PI3Ks), and the Hsp90 molecular chaperone. The reader is also referred to previous personal views from this author in published interviews (Workman 2001(Workman , 2003c. CANCER KINOME TARGETSOncogenic kinases clearly punch above their weight in the league tables of cancer genes. Of the 291 cancer-causing genes identified in a recent census, 27 (6%) encode protein kinase domains, much higher than the 6 (2%) that would be predicted on the basis of random selection (Futreal et al. 2004). The druggability of kinases as a target class is confirmed by the examples listed in the previous section of this paper. As mentioned, both antibodybased and small-molecule approaches to drugging the cancer kinome have been successful. Kinases now represent the most frequently targeted gene classes in cancer and are second only to G-protein-coupled receptors when ranked across all therapeutic areas (Cohen 2002;Hopkins and Groom 2002).This has stimulated interest to search for new drug targets among the 518 putative kinases in the human genome (Cohen 2002;Manning et al. 2002). The earliest kinase targets represented the results of decades of painstaking biological research. On the basis of a large body of work, we now know that kinases can be activated in cancer by mutation, translocation, amplification, overexpression, and posttranslational modification. The discovery of kinase targets has recently benefited from the availability of the complete human genome sequence (International Human Genome Sequencing Consortium 2004) and the application of gene expression profiling by microarray, together with high-throughput mutation detection and high-throughput sequencing approaches (Weir et al. 2004;.In the first breakthrough made by high-throughput cancer genome sequencing, activating mutations in B-RAF were identified, particularly in melanoma but also in papillary thyroid, serous ovarian, and other cancers (Davies et al. 2002;Garnett and Marais 2004). This discovery immediately stimulated the evaluation in malignant melanoma of sorafenib (formerly known as BAY 43-9006; see Fig. 2), a multi-targeted kinase inhibitor that blocks B-RAF and ...

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