DTP Branches and Offices
Discovery of Novel Compounds with a Particular Mechanism
The results obtained by analyzing standard agent mean graph patterns with the COMPARE algorithm strongly indicate that these patterns often reflect the mechanism of action by which chemical substances act upon cells in vitro. As a consequence, COMPARE can be used to help achieve important goals of the DTP in vitro antitumor drug screening program, such as identification of newly screened compounds for referral for in vivo antitumor testing in xenograft models.
In the following applications, COMPARE was used to readily provide information never before available to screening programs. With a single COMPARE analysis, requiring approximately 45 s to perform, one can obtain a good estimate as to whether a newly screened chemical acts by a previously recognized antitumor mechanism. The “goodness” of this estimate has not been statistically validated; rather, it is supported by the excellent results obtained with standard agents.
Lead optimization, the type of drug development where medicinal and organic chemists make small modifications to lead structures to improve drug activity, reduce toxicity, and alter other properties, has been an important activity for many research groups and a productive source of clinical drug candidates. COMPARE has the potential to serve a very useful role in this type of analogue development because it can readily determine if a particular new analogue acts by the target mechanism. Numerous structural analogues have been identified by COMPARE as acting by the expected mechanism and referred for in vivo testing.
Inasmuch as COMPARE does not use chemical structure data to select compounds that act by related mechanisms, it can detect structurally novel compounds as readily as analogues provided they act by the same mechanism. COMPARE can thus help identify classes of compounds never before recognized as topoisomerase I or II agents, tubulin-binding agents, antimetabolites of various types, and so on.
For example, numerous newly screened chemicals have been identified with COMPARE as tubulin-binding agents. Independent proof of the tubulin-binding activity was obtained by published laboratory procedures (6, 7). Many of these compounds had structures that were not analogous to those of previously identified antimitotic drugs. Once a new structural class of known mechanism of action is discovered, then additional screening of available analogues and synthesis of additional analogues can be used to define optimal structural features for antitumor activity.
Given that the mechanistic determinations of COMPARE have been validated in these cases by using standard laboratory procedures, it is considered appropriate to use COMPARE determinations, without further laboratory tests for proof, as a basis for requesting in vivo tests of in vitro screened chemicals as part of a continuing screening program evaluation.
Another use of COMPARE is for the analysis of mean graph data of compounds with significant in vivo activity but about which little is known regarding the mechanism of action. Many such compounds have not been tested in the clinic so they are not among the standard agents. It is reasonable to conduct in vivo evaluation on COMPARE matches to these types of undeveloped lead compounds, assuming that similarity of cytotoxicity patterns documented with COMPARE indicates analogous, although unknown, mechanism of action.
A major goal of the new DTP anticancer screening program is to identify compounds with disease subpanel specificity. This means that a compound is significantly more toxic to cells of one, two, or three particular histological subcategories (e.g., colon, renal, melanoma, etc.) than it is to the remainder of the tumor cell panel. A compound with significant subpanel specific toxicity may be of interest without regard to its mechanism of action. Its novelty may even be more interesting if it does not share a mechanism of action with any known agent, and this too can be evaluated by using COMPARE.