Liang, K., Smith, E.R., Aoi, Y., Stoltz, K.L., Katagi, H., Woodfin, A.R., Rendleman, E.J., Marshall, S.A., Murray, D.C., Wang, L., Ozark, P.A., Mishra, R.K., Hashizume, R., Schiltz, G.E., Shilatifard, A. (2018). Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.  Cell 175(3): 766--779.e17.

FBrf0240370

Research paper

The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.

PMC6422358 (PMC) (EuropePMC)