DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase i Inhibitor for Selective Prostate Cancer Cell Targeting

Jyoti Roy, Trung Xuan Nguyen, Ananda Kumar Kanduluru, Chelvam Venkatesh, Wei Lv, P. V.Narasimha Reddy, Philip S. Low, Mark Cushman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

(Figure Presented). Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.

Original languageEnglish (US)
Pages (from-to)3094-3103
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number7
DOIs
StatePublished - Apr 9 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase i Inhibitor for Selective Prostate Cancer Cell Targeting'. Together they form a unique fingerprint.

Cite this