Author: Wieslaw M. Cholody ; Brian I. Carr ; Meifang Wang ; Anne Monks ; Humcha K. Hariprakasha ; Christopher J. Michejda ; Teresa Kosakowska-Cholody ; Siddhartha Kar

HKH40A (RTA 502), an optimized 8-methoxy analog of the unsymmetrical bifunctional antitumor agent WMC79, was found to be potently active against liver cancer cell growth in vitro and in vivo. Studies on selected human hepatocellular carcinoma (HCC) cell lines with differing p53 status (HepG2, Hep3B, and PLC/PRF/5), revealed that drug-mediated growth inhibition was independent of p53 status. FACS analysis showed an accumulation of cells in S-phase within 24 h of treatment with 100 nM HKH40A. Subsequent incubation of cells, either in the presence of drug or without, caused cell cycle block at the S and G2/M checkpoints, which was consistent with the observed up-regulation of p21, cyclin A, cyclin B1, sustained phosphorylation of Cdk1, and down-regulation of Cdc6, Cdc7, and RRM2. This irreversible growth arrest eventually led to apoptosis. HKH40A completely suppressed growth of the rat transplantable HCC cell line (JM-1) in an orthotopic model in Fisher 344 rats in vivo, without evidence of toxicity. HKH40A may be a useful agent for new therapeutic strategies focusing on inhibition of HCC cell proliferation.

01 Nov 2007·Journal of Medicinal ChemistryQ1 · MEDICINE

Optimization of Naphthalimide-imidazoacridone with Potent Antitumor Activity Leading to Clinical Candidate (HKH40A, RTA 502)

Q1 · MEDICINE

Article

Author: Stinson, Sherman F. ; Tarasova, Nadya I. ; Cholody, Wieslaw M. ; Michejda, Christopher. J. ; Hariprakasha, Humcha K. ; Kosakowska-Cholody, Teresa ; Meyer, Colin

Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activity against xenografts of human colon and pancreatic tumors in athymic mice.

30 Nov 2006·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Biological Evaluation of New Asymmetrical Bisintercalators as Potential Antitumor Drugs

Q1 · MEDICINE

Article

Author: Santoni, Giorgio ; Sparapani, Silvia ; Magnano, Amelia ; Antonini, Ippolito ; Lucciarini, Roberta ; Amantini, Consuelo

The good results obtained in the past decade with various types of potential bisintercalating agents, e.g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 (Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t (Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	National Cancer Institute	30 Jun 2005

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