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.

Antitumor activity of novel POLA1-HDAC11 dual inhibitors / S. Dallavalle, L. Musso, R. Cincinelli, N. Darwiche, S. Gervasoni, G. Vistoli, M.B. Guglielmi, I. La Porta, M. Pizzulo, E. Modica, F. Prosperi, G. Signorino, F. Colelli, F. Cardile, A. Fucci, E.L. D'Andrea, A. Riccio, C. Pisano. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 228(2022 Jan 15), pp. 113971.1-113971.18. [10.1016/j.ejmech.2021.113971]

Antitumor activity of novel POLA1-HDAC11 dual inhibitors

Dallavalle S.;Musso L.;Cincinelli R.;Gervasoni S.;Vistoli G.;Modica E.;
2022-01-15

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.
DNA polymerase α; HDAC11; Histone deacetylases; Interferon-α; p53 acetylation; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; DNA Polymerase I; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Structure-Activity Relationship; Tumor Cells, Cultured
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0223523421008205-main.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 4.06 MB
Formato Adobe PDF
4.06 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/903664
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact