Ohnmacht Stephan A, Marchetti Chiara, Gunaratnam Mekala, Besser Rachael J, Haider Shozeb M, Di Vita Gloria, Lowe Helen L, Mellinas-Gomez Maria, Diocou Seckou, Robson Mathew, Šponer Jiri, Islam Barira, Pedley R Barbara, Hartley John A, Neidle Stephen
UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Sci Rep. 2015 Jun 16;5:11385. doi: 10.1038/srep11385.
We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.
我们在此报告，一种四取代萘二亚胺衍生物（MM41）对MIA PaCa - 2胰腺癌异种移植模型具有显著的体内抗肿瘤活性。以每周两次、15 mg/kg的剂量静脉给药，在一组荷瘤动物中可使肿瘤生长减少约80%。两只动物在279天后无瘤存活。高水平的MM41能迅速转运至细胞核，并在肿瘤中积累。MM41是一种与四链体相互作用的化合物，它与BCL - 2和k - RAS基因启动子序列中编码的四链体强烈结合，这两个基因在许多人类胰腺癌中均失调。与对照组相比，MM41处理动物的肿瘤中BCL - 2水平降低了约40%，这与BCL - 2是MM41的靶点一致。分子模拟表明，MM41与BCL - 2四链体的结合方式类似于先前在与人端粒四链体的共晶体结构中观察到的方式。这支持了MM41（以及其他靶向四链体的小分子）能够结合多个基因中形成四链体的启动子区域并下调其转录的概念。我们认为，那些在特定癌症中作为上调驱动因子的主基因内的四链体，可能是MM41等化合物的选择性靶点。
