The Kinome and its Impact on Medicinal Chemistry

DAVID H. DREWRY, PAUL BAMBOROUGH, KLAUS SCHNEIDER AND GARY K. SMITH

1.1 Introduction

The "Kinome" describes the protein kinase component of the human genome, exhaustively compiled in 2002 by Manning et al. A search of available human sequence sources using a hidden Markov model identified 478 ePK (eukaryotic protein kinase) genes, 491 ePK domains, and 40 "atypical" protein kinases. The tree-like classification developed from this has become the defining image in the field of protein kinase pharmaceutical research and has been used as the framework for the display of numerous properties. The ePKs are subdivided into eight main groups (Table 1.1), extending the previous classification of Hanks and Hunter.

For the last few years protein kinases have been among the most actively studied pharmaceutical targets. In 2005 it was estimated that around one in three discovery efforts targeted protein kinases. Federov et al. surveyed the landscape of kinase inhibitor publications and patents, and noted that the number of patents declined from 2006–2009, perhaps suggesting that industrial research is moving on to other areas, although this could also show that it is becoming increasingly difficult to differentiate novel compounds from prior art. However, it was also found that not all kinases have received equal attention and that the majority of protein kinases have not been studied at all. A similar trend is seen when the count of compounds from journals and patent literature, rather than the number of publications, is plotted on the kinome tree as shown in Figure 1.1 [Illustration reproduced courtesy of Cell Signaling Technology, Inc. (http://www.cellsignal.com)]. Certain tyrosine kinases, CMGC kinases, and AGC kinases have been intensively studied. In contrast, the majority of kinases have no published activity data whatsoever. A significant number of targets have no published inhibition data apart from the small number of compounds arising from high throughput profiling efforts. It is also apparent that these "untouched" kinases are unevenly distributed and that there are entire branches of the kinome tree for which small molecule inhibitors are unknown. Targets for which inhibitors exist with the selectivity necessary to make them useful tool compounds are even fewer. This distribution probably mirrors the body of literature describing the functions of these kinases, of which ~50% are said to be largely uncharacterised. Many kinases still have unknown function, and as a result there has been little incentive to seek to develop inhibitors.

This pattern is partly repeated when the analysis is restricted to the ten kinase inhibitors (Figure 1.2) that have been approved and marketed (Table 1.2). At least so far as it is possible to judge from the published stories of their discovery, nine out of the ten drugs were originally conceived as inhibitors of various tyrosine or tyrosine-like kinases. With evolution in screening technology it is possible to profile these clinical compounds against an ever expanding list of kinases. They are generally less selective than initial reports suggested, but range from the highly selective, such as Lapatinib, which targeted EGFR and ErbB2, to the fairly promiscuous, such as Sunitinib, which bound to multiple kinases.

These compounds share another feature in common besides the intent to inhibit tyrosine kinases. Nine of the ten kinase drugs are approved for oncology indications. Whilst the clinical attrition rate of kinase compounds is significantly lower than that for other antitumor agents, there are few examples of success for other indications to date. Fasudil, an inhibitor of ROCK (an AGC family kinase) is the exception, approved for acute cardiovascular disease in Japan. To some extent this may indicate that there has been a greater focus on cancer indications in kinase R&D organizations, perhaps because these are now precedented targets. This cannot be the whole story, since considerable effort has been expended in other areas, notably for inflammatory diseases.

On the positive side, if drugs for chronic conditions can be developed, they should not suffer from the problems of emerging resistance that have plagued kinase oncology drugs. However, there are significant challenges that must be overcome before kinase inhibitors can be useful for chronic diseases. The first limiting factor is the understandable unwillingness to accept risks of side-effects in chronic disease that may be acceptable in severe acute illness. All medications may suffer from on-target side-effects, but kinase drugs seem more likely than most to suffer from unexpected off-target effects because of their closely related binding sites and well-established cross-activity. A secondary problem is that a chronic disease treatment may place a greater importance on oral, twice-daily dosing in a tablet form than acute disease. To some extent these two factors may be related. Many of the cancer compounds listed in Table 1.2 have relatively high molecular weights compared to the average for oral drugs of 337. Presumably this has been brought about in part by the need to build in extra features in order to achieve greater kinase selectivity. Compounds targeting the inactive DFG-out and C-helix-out conformations are often especially large. Larger molecules generally have poorer pharmacokinetic properties, so if indeed larger molecules are needed to attain the requisite selectivity, it may be harder to find orally active compounds with appropriate selectivity for chronic diseases.

This may be made harder still depending on the choice of primary kinase target. It has been shown that tyrosine kinase inhibitors are more likely to show cross-inhibition of moderately closely related kinases than are inhibitors of CMGC kinases, for example. In the case of chronic diseases demanding a low-risk profile and greater selectivity, the historical emphasis on tyrosine kinases as targets might have contributed to the low success rate. Yet, with a few exceptions, target validation for most kinases on other kinome branches has been slower to emerge.

Table 1.3 lists some promising compounds in development for inflammation, and structures are shown in Figure 1.3. The furthest...