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. 2021 Feb 11;22(4):1794. doi: 10.3390/ijms22041794

Table 1.

Akt inhibitors in the management of HCC.

Inhibitor Mechanism of Action, Structure Experiment Setup Antitumor Effect Effect on TME Clinical Trial
GDC-0068
[64,65,66]		 ATP competitive AKT inhibitor
Inline graphic 		Combination of GDC-0068 with Sorafenib in HepG2 and Huh7 sorafenib-resistant cell-lines
  • -

    synergistic antitumor effect

  • -

    promotion of apoptosis

  • -

    induction of

  • -

    autophagic cell death

 Not investigated Phase-I/II including multiple solid tumors treated by GDC-0068 in monotherapy or in association with abiraterone + prednisolone: safe and tolerable in monotherapy or in combination
AZD5363
[67,68]		 ATP competitive AKT inhibitor
Inline graphic 		Single agent in HepG2 and Huh-7 HCC cells Combination with FH535 (β-catenin inhibitor) in THH, Hep3B and HepG2
  • -

    inhibition of tumor proliferation

  • -

    induction of cell-cycle arrest

  • -

    promotion of apoptosis

  • -

    promotion of autophagy through p53 activation

 Not investigated Phase-I, AZD5363 in monotherapy, in multiple advanced solid tumors including liver cancer (NCT01895946): safe and tolerable, no data on antitumor response
Phase-I including multiple solid tumors harboring AKT mutations (NCT02465060)
ARQ 092
[69,70]		 allosteric pan-AKT inhibitor
Inline graphic 		Single agent and in combination with Sorafenib in a DEN-induced cirrhotic rat model of HCC and in Hep3B, HepG2, Huh-7, PLC/PRF, and HR4 HCC cell lines
  • -

    inhibition of tumor proliferation

  • -

    promotion of apoptosis

  • -

    synergistic antitumor effect when combined with sorafenib
  • -

    anti-angiogenic effect

  • -

    improved liver fibrosis

  • -

    decrease of intrahepatic neutrophils and macrophages

 No clinical trial
ARQ 751
[71]		 allosteric pan-AKT inhibitor
Chemical structure of ARQ 751 is currently unavailable.		 Single agent and in combination with sorafinib in DEN-induced cirrhotic rat model of HCC
  • -

    inhibition of tumor proliferation

  • -

    synergistic antitumor effect when combined with sorafenib
  • -

    Improved liver fibrosis

 Phase-Ib (NCT02761694)
in solid tumors with PIK3CA/AKT/PTEN mutations including HCC: ongoing
MK-2206
[72,73]		 allosteric pan-AKT inhibitor
Inline graphic 		Single agent in Human Huh7, Hep3B, and HepG2 HCC cell lines
  • -

    Promotion of apoptosis

  • -

    Inhibition of cell proliferation

  • -

    Induction of cell cycle arrest

 Not investigated Phase-II trial, MK-2206 in monotherapy in advanced HCC previously treated
(NCT01239355): discontinued due to discouraging results