Platinum-Acridine Chemotherapeutics for Intractable Cancers

Wake Forest University’s cytotoxic platinum–acridine chemotherapeutics have been shown in preclinical models to effectively kill cancer cells that are inherently resistant to chemotherapy or have developed resistance over time. This includes a wide range of solid tumors, including lung, ovarian, breast and pancreatic cancers, as well as hematological malignancies, such as multiple myeloma.

This new class of platinum-acridine chemotherapeutics has significant potential for tackling highly advanced and chemoresistant malignancies. Traditional platinum-based chemotherapies are a mainstay of many cancer treatments, but systemic toxicity and various forms of resistance limit their efficacy. Wake Forest’s novel platinum-acridine anticancer agent builds on the known efficacy of platinum-based therapies, improving the profile of these compounds by overcoming drug resistance and increasing cancer-killing potency. The structurally unique compound has improved intracellular concentrations and DNA binding affinity, enabling it to target and destroy cancer cells at lower overall doses than existing platinum-based therapies.

Competitive Benefits

  • 500 x the cytotoxicity of cisplatin in NCI-H460 cell proliferation assays, with IC50 values in the nanomolar range
  • Significantly reduced tumor growth in a highly aggressive H460 mouse xenograft model at doses lower than typical for cisplatin
  • Excellent cytotoxic response in cancers resistant to conventional platinum therapy
  • Rapid intracellular accumulation in tumor cells and higher DNA adduct levels lead to efficient cancer cell kill
  • Excellent chemical versatility for modification with conjugatable functional groups using click chemistry
  • Localization of drugs in nucleoli and possibility of targeting “nucleolar rRNA synthesis,” by stabilizing telomeric G-quadruplex DNA structures and inhibition of telomerase enzyme activity
  • An emerging target in anticancer drug development

Application Fields

  • An effective first- or second-line therapy for many solid tumor malignancies
  • Demonstrated efficacy against chemoresistant non-small cell lung cancer (NSCLC)
  • Compatible with liposomal nanoencapsulation for safe delivery and co-delivery with targeted antibody and/or chemosensitizing agents in the form of cleavable conjugates

Status

  • Several compounds chemically and biologically fully characterized
  • Synthetic procedures optimized; robust and amenable to high-throughput screening
  • In vivo study completed and published, with additional in vivo studies underway
  • Issued Patent US20120039800
  • PCT/US09/061832 (nationalized in Canada, the European Patent Office, and Japan)
  • PCT/US2012/053189

Inventors

Ulrich Bierbach, PhD

Publications

J. Med. Chem. 2008, 51, 7574-7580
“Expanding Platinum’s Potential. Paradigm Shift.” Nature/SciBx 2008, 1, 1-3
ACS Med. Chem. Lett., 2011 Sep 8; 2(9): 687-691
Metallomics, 2012, 4, 645-652
J. Med. Chem., 2012, 55, 7817-7827
J. Med. Chem., 2012, 55, 10198-10203

Licensing Contact

Stephen Susalka, PhD
Associate Director, Commercialization
+1.336.716.4029
ssusalka@wakehealth.edu

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