Targeting Ubiquitin-Mediated Degradation for Proliferation Inhibitors

Abstract

The possibility of developing small molecule cancer chemotherapeutics using mechanism-based drug design has only recently been considered. The anti-cancer drugs presently available to the clinic were initially discovered as substances that inhibit the proliferation of tumors in animal models and/or of cultured cells (see ^1,2 for reviews). The field of cancer chemotherapy started with the serendipitous discovery that mustard gas agents used in chemical warfare induced lymphoid hypoplasia, leading the way to their use in the treatment of Hodgkin’s and lymphocytic lymphoma. The availability of transplantable tumor models in laboratory animals was also of utmost importance to allow testing of novel chemical agents. The establishment of a mass screening effort at the US National Cancer Institute (NCI) to identify substances that inhibit the proliferation of cultured tumor cells, then led to the discovery of agents that have been useful to treat and cure certain tumors, including leukemias and lymphomas. The NCI approach has primarily focused on the identification of chemical entities that inhibit the proliferation of one or the other histological cell type. With the discovery of the multiple drug resistance (MDR-1) gene and its amplification in tumors, some cell lines that show MDR-1 amplification in addition to their parental lines were introduced into the screen, but still, to this date most of the NCI screening efforts have focused on the identification of novel compounds that inhibit cell proliferation with a distinctive pattern. The identification of the molecular targets of the available anti-cancer drugs, together with the explosion in the discovery of genetic and biochemical abnormalities in cancer cells have suggested the possibility of taking a molecular mechanism-based approach for the development of cancer therapeutics (see³, for review).