Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models

Abstract

Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetrasubstituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/β-catenin signaling.

G-quadruplexes: a promising target for cancer therapy

“… 50% decreased tumor growth of MIA-Pa-Ca2 xenografts No in vitro cyto-toxicity assay done x [ 168 ] C14 PANC-1 n.a. IC 50 : ~10 nM when irradiated with halogen light x [ 141 ] C-2028 PANC-1, MIA PaCa-2, BXpC-3, AsPC-1, Capan-2 72 h IC 50 for all cell lines < 100 nm About 80% reduced Panc-1 xenograft growth in vivo x [ 170 ] CM03 MIA PaCa-2, PANC-1 96 h IC 50 : 7 nM (MIA), 18 nM (PANC-1), reduced tumor growth by ~ 73% x [ 171 – 173 ] Copper(ii) l/d-valine-(1,10-phen) complexes (complex 1a, 1b) BxPC3, AsPC1 72 h IC 50 : ~2 μM for both complexes in both cell lines x [ 174 ] CX-3543 (Quarfloxin) MIA PaCa-2 n.a. >50% reduced tumor growth of MIA PaCa-2 xenografts x x [ 129 ] CX-5461 Gemcitabine-resistant MIA PaCa-2 (GemMIA-R3) and normal MIA-PA-Ca2 96 h GI 50 : 90.3 nM (GemMIA-R3), 88.7 nM (MIA-Pa-Ca2) x [ 175 ] MM41 MIA PaCa-2, PANC-1 96 h IC 50 : 11 nM (MIA), 3 nM (PANC-1), ~80% reduced growth of MIA PaCa-2 xenografts in vivo x [ 163 , 171 ] Naphthalene diimide ligands (compounds 3d, 3h) …”

A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells

“…To our knowledge, the present study is the first to report synergy between a quadruplex compound and a chemotherapeutic agent in pancreatic cancer cells, and future studies will extend these to in vivo models for the disease. CM03 alone has in vivo activity but a narrow therapeutic window, which it has in common with several other quadruplex binding compounds [ 7 , 8 , 9 , 52 , 53 , 54 ]. Although data for in vivo maximum tolerated doses are not always available, a consistent trend for narrow therapeutic windows is apparent (an exception is the substituted perylene compound EMICORON [ 55 ]).…”

“…Although data for in vivo maximum tolerated doses are not always available, a consistent trend for narrow therapeutic windows is apparent (an exception is the substituted perylene compound EMICORON [ 55 ]). CM03, with cellular GI 50 values of 10–15 nM in PDAC cell lines ( Table 1 ), is active in xenograft and genetic PDAC models at biweekly doses of 10–15 mg/kg [ 8 , 9 ]. The present synergy study, with CM03 active in both parental and chemo-resistant cells at concentration down to ca 5 nM and showing cell growth arrest of >50% in synergy with SAHA, suggests that a three-fold reduction of in vivo CM03 dosage to ca 3–5 mg/kg may have a significant anti-tumor effect when in combination with SAHA.…”

“…The present synergy study, with CM03 active in both parental and chemo-resistant cells at concentration down to ca 5 nM and showing cell growth arrest of >50% in synergy with SAHA, suggests that a three-fold reduction of in vivo CM03 dosage to ca 3–5 mg/kg may have a significant anti-tumor effect when in combination with SAHA. This would enlarge the therapeutic window of both compounds, especially CM03, which has been shown to downregulate key genes in PDAC progression [ 8 , 9 ].…”

“…We have recently developed a class of potential drugs for PDAC that are based on the naphthalene diimide (ND) chemotype [ 3 , 4 ]. The lead compounds CM03 and SOP1812 have shown profound in vitro anti-proliferative activity in pancreatic cancer cell lines and significant in vivo anti-tumour activity in several PDAC models, with an improved profile compared to gemcitabine [ 5 , 6 , 7 , 8 , 9 ]. These compounds bind to G-quadruplexes in vitro and in cells, and their mechanism of action is considered to involve the inhibition of cancer gene function by binding to regulatory quadruplex elements in these genes.…”