Abstract 965: Identification of KJ-Pyr-9 as a potent MYC inhibitor

Abstract

Abstract We have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. KJ-Pyr-9 functions as an inhibitor of MYC in biochemical assays, in cells and in xenograft experiments. In vitro, KJ-Pyr-9 binds to MYC as well as MYC-MAX dimers and can disrupt binding of MYC-MAX dimers with E-box DNA. In cells, MYC-MAX dimerization can be disrupted in cells as demonstrated by protein fragment complementation assays. KJ-PYR-9 disrupts the transcriptional targets of MYC. The P493-6 cell line has tetracycline regulatable MYC expression. For this cell line, the transcriptional targets of MYC can be readily observed upon the addition of 0.1 ug/mL doxycycline. Both doxycycline and KJ-PYR-9 negatively regulate MYC transcriptional signatures as determined by GSEA. The growth of a variety of different MYC-dependent cell lines are inhibited, including MYC translocated Burkitt's lymphoma cell lines expressing high levels of MYC as well as solid tumor cell lines expressing moderate amounts of MYC. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells. Citation Format: Jonathan R. Hart, Klaus Bister, Kim D. Janda, Peter K. Vogt. Identification of KJ-Pyr-9 as a potent MYC inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 965. doi:10.1158/1538-7445.AM2015-965