Abstract 194: Effective targeting of MYC expression with a novel nucleic acid binding (G4-quadruplex) small molecule coupled with HDAC inhibition synergizes to limit myeloma growth
| Autor: | Zaw Phyo, David R. Calabrese, Elena C. Leon, Daniel Connors, John K. Simmons, Beverly A. Mock, Shuling Zhang, John S. Schneekloth, Snehal M. Gaikwad, Aleksandra M. Michalowski, Sayeh Gorjifard |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:194-194 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | MYC is deregulated in many malignancies and its aberrant expression is associated with tumorigenesis and tumor maintenance. We employed a therapeutic strategy to target both MYC transcription, and protein stability. Previously, we developed a small molecule microarray and screened it for MYC G4-binding compounds. The stabilization of G-quadraplex (G4) structures by nucleic acid binding small molecules in the NHE III region of the MYC promoter slows MYC transcription. We identified a benzofuran containing small molecule that could selectively and reversibly stabilize MYC-G4 DNA and reduce MYC expression. This compound demonstrated a G4-dependent mechanism of action showing toxicity in multiple myeloma cell lines containing a G4 in their MYC promoter whereas minimal effects were seen in a Burkitt’s lymphoma line lacking the MYC G4 sequence. Gene expression analysis validated that this compound selectively inhibited MYC and other MYC effectors, but did little to limit the expression of other G4 containing genes. The synthesis of more than 15 analogs identified a new benzofuran-containing analog with enhanced inhibitory activity in a diverse panel of human cancer cell lines (NCI-60), including a number of myeloma cell lines. EDGE-seq data confirmed that the new analog is similar to the original compound in having higher affinity for the G4 in MYC compared to the G4 in BCL2, KRAS, VEGFA and HIF1A. In addition, the analog was synergistic with entinostat, an HDAC inhibitor that can affect MYC protein stability, in limiting myeloma cells, but not PBMCs. The more potent growth inhibitory activity of the new analog allowed us to generate sufficient quantities to evaluate its pharmacokinetics and toxicity in mice. The compound was well tolerated in a dose-escalation toxicity study; no adverse effects were observed and preliminary pharmacokinetic studies showed promising serum bioavailability and exposure properties when administered either intravenously, intraperitoneally or orally. In an assessment of short term in vivo activity, MYC protein expression was inhibited in multiple myeloma xenografts. Longer term studies to evaluate the anti-tumor activity of the compound are currently in progress. Thus, our data provide evidence that small molecule stabilization of the MYC G4 can drive transcriptional silencing of oncogenic MYC both in vitro and in vivo. Furthermore, synergistic tumor cell killing was achieved when the MYC G4 inhibitor was coupled with HDAC inhibition. Citation Format: Snehal M. Gaikwad, David R. Calabrese, Elena C. Leon, John K. Simmons, Shuling Zhang, Aleksandra Michalowski, Sayeh Gorjifard, Zaw Phyo, Daniel Connors, John S. Schneekloth, Beverly A. Mock. Effective targeting of MYC expression with a novel nucleic acid binding (G4-quadruplex) small molecule coupled with HDAC inhibition synergizes to limit myeloma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2017-194 |
| Databáze: | OpenAIRE |
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