Because mutations of splicing factor 3B subunit-1 (SF3B1) have been identified in 4% of pancreatic ductal adenocarcinoma (PDAC) patients, we investigated the activity of new potential inhibitors of ...SF3B1 in combination with gemcitabine, one of the standard drugs, in PDAC cell lines.
One imidazo2,1-
1,3,4thiadiazole derivative (IS1) and three indole derivatives (IS2, IS3 and IS4), selected by virtual screening from an in-house library, were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2, Hs766t and Panc05.04, the latter harbouring the SF3B1 mutations. The effects on the splicing pattern of proto-oncogene recepteur d'origine nantais (RON) and the gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT1) were assessed by PCR, while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.
The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death. All compounds showed an interesting anti-migratory ability, associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure. Moreover, IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in hENT1 expression (
< 0.05
. untreated control cells), potentially reversing PDAC chemoresistance.
These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
A series of new 3-amino-
N-phenyl-1
H-indazole-1-carboxamides
10 have been prepared from commercially available phenyl isocyanate precursors
8 and 3-aminoindazole
9. Some of the synthesized compounds ...were evaluated for their in vitro antineoplastic activity against 60 human cell lines derived from seven clinically isolated cancer types (lung, colon, melanoma, renal, ovarian, brain, and leukemia) according to the NCI standard protocol. The test results indicated that 3-amino-1
H-indazole-1-carboxamides
10 were endowed with an interesting antiproliferative activity. The most active compounds of this series,
10d,
e, were able to inhibit cell growth of many neoplastic cell lines at concentrations lower than 1
μM (0.0153
μM in SR leukemia) causing a block in G0–G1 phase of cell cycle. Analysis of pRb expression showed that these two compounds increased the ratio between underphosphorylated pRb and total pRb. The X-ray structure of
10w, confirmed the 3-amino-
N-phenyl-1
H-indazole-1-carboxamide structure of compounds
10.
Display omitted The reaction of 3-amino-
N-phenyl-1
H-indazole with the appropriate phenyl isocyanate derivatives afforded compounds
10–
12. The test results indicated that 3-amino-1
H-indazole-1-carboxamides
10 were endowed with an interesting antiproliferative activity. They cause a block in the G0–G1 phase of cell cycle and increase the ratio between underphosphorylated pRb and total pRb.
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