Small molecule anticancer drugs.
Currently there is an intensive drug discovery effort aimed at introducing more selective cancer drugs into the clinic which exploit various targets emerging from the increasing molecular understanding of the disease. Examples include inhibitors of the RAS processing enzyme, farnesyl transferase, the first of which, R115777 (Janssen Pharmaceutica BV) and L778123 (Merck & Co) have entered phase I. In both cases, myelosuppression was dose-limiting; evidence of antitumor activity has been observed with R115777. There is a lot of interest in targeting cyclin-dependent kinases (cdk): flavopiridol (Hoechst AG), a broad-spectrum inhibitor of cdk1, cdk2 and cdk4 is now entering phase II trials. However, in the above two cases, it is now not clear that the in vivo effects of these molecules are due to specific effects against their originally proposed targets. More selective cdk inhibitors are under development. Other targets being studied at the preclinical level, which may result in new therapies in the next five years, are inhibitors of telomerase, MDM2 and c-Raf.
Kelland
L R
LR
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, SM2 5NG, Surrey, United Kingdom. lloyd@icr.ac.uk