Molecules for the millennium: how will they look? New drug discovery year 2000

Abstract

A new approach to cancer drug discovery targets molecules important in cancer pathogenesis. This approach is thought to be of greater promise than the antiproliferative screens which discovered cytotoxic agents and dominated cancer drug discovery for 60 years. However, one cannot lose sight of the fact that these targets exist in the cellular environment consisting of many additional influences on target function, and that effective drug treatment will take into account drug uptake, metabolism and elimination at the level of the cell as well as the organism. A key goal is to define for the new millennium a path to cancer drug discovery and development which accounts for the cancer cell phenotype in its totality rather than as arising solely from single molecular targets. The US National Cancer Institute maintains a cell-based drug discovery screen which can define a context for drug action in the milieu of more than 300 molecular targets and thousands of gene expression patterns which have been measured in the 60 human tumour cell lines which comprise the screening panel. The challenge of the millennium will be addressed by molecules active against defined targets but with selectivity of action occurring in the milieu of deregulated cancer cell biology in all its aspects. © 2000 Cancer Research Campaign http://www.bjcancer.com

SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

“…These data are then plotted as mean bar graphs and as dose-response curves. COMPARE and molecular target analyses were performed as a means to identify similarities with other known or experimental chemotherapeutic agents (18) and to determine whether there is evidence for alignment with patterns of cell line gene expression (19).…”

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

“…COMPARE analysis [31,32,33,34,35,36] was then performed for compounds 5 – 15 against the NCI Standard Agents list, an aggregate of 171 compounds that have shown clinical antiproliferative activity. The analysis returns a Pearson correlation coefficient (PCC; [37,38]) that ranges from −1.0 to 1.0, representing the statistical similarity of a compound, compared to the activity of the known standard with 1.0 representing a perfect match, and −1.0 representing a perfect mirror image of the compared activities [31].…”

Cancer Metabolism: Strategic Diversion from Targeting Cancer Drivers to Targeting Cancer Suppliers

“…Sidney Farber’s study of the effects of folic acid on pediatric leukemia led to the development of antifolates as anticancer drugs. His findings generated an effective anti-leukemic drug, although the functional mechanism remained unknown ( Sausville and Johnson, 2000 ; Chabner and Roberts, 2005 ). Successes with nitrosourea drugs and antifols led to the development of new drugs based on analogs of these compounds ( Jackson, 1987 ).…”