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

  • Nat Commun. 2014 Oct 1;5:5086. doi: 10.1038/ncomms6086.
Wei Wang  1 ,  Jiang-Jiang Qin  2 ,  Sukesh Voruganti  2 ,  Kalkunte S Srivenugopal  3 ,  Subhasree Nag  2 ,  Shivaputra Patil  4 ,  Horrick Sharma  4 ,  Ming-Hai Wang  3 ,  Hui Wang  5 ,  John K Buolamwini  4 ,  Ruiwen Zhang  1
Affiliations
  • 1. 1] Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
  • 2. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
  • 3. 1] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • 5. Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
PMID: 25271708 DOI: 10.1038/ncomms6086
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.

Products