The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models

Wei Wang, Jiang-Jiang Qin, Sukesh Voruganti, Kalkunte S. Srivenugopal, Subhasree Nag, Shivaputra Patil, Horrick Sharma, Ming-Hai Wang, Hui Wang, John K Buolamwini () and Ruiwen Zhang ()
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Wei Wang: School of Pharmacy, Texas Tech University Health Sciences Center
Jiang-Jiang Qin: School of Pharmacy, Texas Tech University Health Sciences Center
Sukesh Voruganti: School of Pharmacy, Texas Tech University Health Sciences Center
Kalkunte S. Srivenugopal: Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center
Subhasree Nag: School of Pharmacy, Texas Tech University Health Sciences Center
Shivaputra Patil: College of Pharmacy, University of Tennessee Health Science Center
Horrick Sharma: College of Pharmacy, University of Tennessee Health Science Center
Ming-Hai Wang: Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center
Hui Wang: Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
John K Buolamwini: College of Pharmacy, University of Tennessee Health Science Center
Ruiwen Zhang: School of Pharmacy, Texas Tech University Health Sciences Center

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2–p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease.

Date: 2014
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DOI: 10.1038/ncomms6086

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