Identifying the next generation of anticancer drug targets


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Bob Jackson

Pharmacometrics Ltd, Cambridge, UK

Abstract

Identifying the next generation of anticancer drug targets

Greater understanding of the molecular biology of cancer has stimulated discovery of a new generation of drugs, targeted at growth factor receptors, oncoproteins, and signalling pathways. In a few cases (e.g. bcr-abl) a qualitative difference in the transformed cell provides a clear basis for selectivity, but in most cases a strong rationale for selectivity is lacking. Often, the selectivity is an emergent property that can only be understood at a higher level of biological organization than the drug-target interaction. An example is the case of seliciclib (R-roscovitine) which was designed as an inhibitor of cdk2. Study of the biological effects of seliciclib showed that the lethal event was inhibition of transcription resulting from inhibition of cdk9 and cdk7. Inhibition of transcription is not an inherently selective effect, but cells that lacked a functional G1 checkpoint (of which cdk2 is an essential component) were particularly sensitive, as evidenced by the fact that seliciclib is non-myelosuppressive. The tumour spectrum of the agent appears to be determined by the dependence of tumour cells on particular rapidly turning-over transcripts: e.g. B-CLL cells are often immortalized by upregulation of the anti-apoptotic protein, Mcl-1 (which turns over very rapidly) and this malignancy is particularly sensitive to inhibition of transcription. Thus, although the molecular target of seliciclib is cdk9 (and perhaps cdk7), its selectivity can only be understood as a function of (at least) three proteins: cdk9, cdk2, and Mcl-1. The lesson for the design of next-generation anticancer drugs is that target selection must begin from an understanding of the system properties of the target, and we will design better drugs, and develop them more rationally, if the basis for their selectivity is understood from the outset. A concept that can shift the focus of drug discovery from potency to selectivity is synthetic lethality, as implemented in synthetic lethal screening. Another concept that can point to selective vulnerabilities of transformed cells is the phenomenon of oncogene addiction. Finally, a systems biology approach to target selection will enable the higher-level effects of inhibition of particular molecular targets to be more accurately predicted: recent work on computational modelling of signalling pathways will be cited as an example of our growing understanding of the emergent phenomenon of drug selectivity.

Declaration of competing interest: Bob Jackson is a Consultant to Cyclacel Ltd.