CX-5461 dihydrochloride

Description: CX-5461 dihydrochloride is a novel, potent, selective and orally bioavailable inhibitor of rRNA synthesis, it selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM in HCT-116, A375, and MIA PaCa-2 cells, has no effect on Pol II, and possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation. CX-5461 was revealed to inhibit Pol I transcription via promoting the stabilization of p53. In addition, CX-5461 has been demonstrated to induce autophagy and senescence but not apoptosis in MIA Paca-2 and A375 cell lines. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, the acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.

References: Cancer Res. 2011 Feb 15; 71(4):1418-30; Oncotarget. 2016 Aug 2; 7(31):49800-49818.

Related CAS#: 1138549-36-6 (free base)