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Ref Type Journal Article
PMID (23215354)
Authors Cinelli MA, Reddy PV, Lv PC, Liang JH, Chen L, Agama K, Pommier Y, van Breemen RB, Cushman M
Title Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase I poisons.
Journal Journal of medicinal chemistry
Vol 55
Issue 24
Date 2012 Dec 27
URL
Abstract Text Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
LMP400 LMP400 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
LMP400 NSC 743400|indotecan TOPO1 inhibitor 8 LMP400 inhibits Top1, resulting in decreased proliferation of tumor cells (PMID: 23215354).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable LMP400 Preclinical Actionable In a preclinical study, LMP400 inhibited proliferation of a variety of human tumor cell lines in culture (PMID: 23215354). 23215354