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Antitumor activity of novel POLA1-HDAC11 dual inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2022 Jan 15; Vol. 228, pp. 113971. Date of Electronic Publication: 2021 Nov 03. - Publication Year :
- 2022
-
Abstract
- Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72-77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Cell Cycle Checkpoints drug effects
Cell Proliferation drug effects
DNA Polymerase I metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors chemistry
Humans
Mice
Mice, Inbred C57BL
Mice, Nude
Molecular Structure
Neoplasms, Experimental drug therapy
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Structure-Activity Relationship
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
DNA Polymerase I antagonists & inhibitors
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 228
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34772529
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113971