A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer

Abstract

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.

Dyads of G‐Quadruplex Ligands Triggering DNA Damage Response and Tumour Cell Growth Inhibition at Subnanomolar Concentration

“…[13] In fact, their optoelectronic properties can be effectively tuned by substituents on the aromatic core, [14] thus giving origin to absorption and emission in the red spectroscopicw indow, which makes them appealing forf luorescence imaging and photodynamic therapy (PDT). [20] More recently,w eh ave published as eries of the NDIs 1-4 (Scheme1)h aving excellentw ater solubility and cellular entry,m erged with promising features for theranostic applications. We and others have shown that tri-and tetra-substituted as well as core-extended NDIs are potent and reversible ligands [14c, 17] and alkylating agentst argeting G-rich nucleic acids (NAs) folded into G4s.…”

Computational Methods to Study G-Quadruplex–Ligand Complexes

“…76,81 A good example is the MD simulation used to study the interactions of tetra-substituted naphthalene diimide compound MM41 and quadruplexes formed in the gene promoter sequences, employing parmbsc0 force field supplemented with χ OL4 modifications. 36 The results from the MD simulations were able to demonstrate the favourable binding mode of MM41 to the BCL-2 quadruplexes. The interactions that MM41 made were analogous to that made by the ligand with human telomeric quadruplex.…”

Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

“…In this regard, it should be taken into account that i) cell factors (e.g., specific G4 interacting proteins) or cell conditions (e.g., chromatin status or transcriptional activity) may impinge on the ligand/G4 interaction, even in a cell-type dependent manner; ii) G4 structures with similar topologies can be amenable of stabilization by the same ligand and that iii) the vast majority of ligands reported thus far to interact with promoter G4s were primarily conceived as telomeric G4 ligands (e.g., telomestatin and RHPS4) [13, 15]. Nonetheless, pieces of evidence indicate that the “promiscuous” nature (i.e., the capability to interacts with multiple G4 targets) of some G4 ligands [11, 13, 31, 34, 35] may be of therapeutic value, as it has been recently shown for an NDI derivative able to simultaneously target the G4 within BCL2 and KRAS gene promoters in an in vivo model of pancreatic cancer [35]. …”