cx-5461

CX5461 是一种 rRNA 合成抑制剂，具有口服活性，可抑制 Pol I 驱动的 rRNA 转录。CX5461 激活 DNA 损伤反应，在卵巢癌等肿瘤中具有抗肿瘤活性。

CX-5461 dihydrochloride 是一种有效的、口服具有活力的 Pol I 介导的 rRNA synthesis 抑制剂，能够作用于 HCT-116 细胞 (IC50: 142 nM)，A375 细胞 (IC50: 113 nM) 和 MIA PaCa-2 细胞 (IC50: 54 nM)，对 Pol II 作用较小 (IC50≥25 μM)。

Pidnarulex HCl is the salt form of CX-5461, a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.

EML-405 is a small-molecule inhibitor of SPIN1 ( Kd of 14 uM).