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

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.

RYBP predicts survival of patients with non-small cell lung cancer and regulates tumor cell growth and the response to chemotherapy

“…Cells were transfected plasmids or infected with AdRYBP or exposed to various concentrations of Paclitaxel, and cell viability, colony formation, and apoptosis assays were performed as described previously [17, 20–23]. …”

“…The protein and mRNA expression of RYBP and related molecules was analyzed by Western blotting and real-time quantitative PCR, respectively [16, 17, 20–23]. Further details can be found in the Supplementary Methods.…”

“…The A549 and H1299 xenograft models were established as described previously [17, 20–23]. The treatment of the animals with AdRYBP and conventional chemotherapy, the evaluation of their tumor growth and clinical status, and the tissue pathology studies are detailed in the Supplemental Methods.…”

“…The HE staining was performed as described previously [17, 22, 23]. In vivo apoptosis was measured by TUNEL staining [17, 22, 23].…”

Outside the p53 RING: Transcription Regulation by Chromatin-Bound MDM2

“…Therefore, designer drugs that completely destabilize MDM2 such as PROTACS (proteolysis activating chimeras) derivatives may offer a new avenue of treatment. Similarly, an MDM2 de-stabilizing compound, SP-141, decreased proliferation of tumor cells even when p53 was mutant (Wang et al, 2014). Drugs that both inhibit p53-MDM2 interaction and destabilize MDM2, or do so in combination, may offer better means of achieving the goal of cancer treatment.…”