Table 1 Potential anti-AML therapeutic approaches with targeting signaling pathways, and metabolic/immune checkpoints

Metabolic related drugs/inhibitirs

3-bromopyruvate and benitrobenrazide

Hexokinase-2

Pyruvate analogs

[359]

2-deoxy-D-glucose (2-DG)

Hexokinase-1

Enhancing the chemotherapeutic drug cytosine arabinoside (Ara-C) sensitivity

[360]

Sorafenib

FLT3

High reliance on glycolysis in murine lymphoid cell line Ba/F3

[361]

6-aminonicotinamide

G6P dehydrogenase

Inducing apoptosis in AML cell lines and primary AML blasts, but not in normal hematopoietic progenitor cells

[362]

Oleanolic acid, Carpesium abrotanoides L, Tanshinone IIA, Dioscin, Polyphyllin VI, Euxanthone, Chrysin

GLUT1, HK2, LDHA, HIF-1α, PFK1, and PKM2

Curable effects on AML cells via affecting glucose enzymes and/or transporters

[260]

Micheliolide (MCL)

PKM2

Selectively activates PKM2 via covalent binding at cysteine424 (C424)

[264]

Venetoclax

BCL-2 protein–protein interaction inhibitor

More efficient in combination of hypomethylating compounds ( decitabine and azacitidine) and reduced Ara-C

[363]

2′3'dideoxycytidine

Inhibiting the mitochondrial DNA replication

A HIV reverse transcriptase inhibitor

[364]

A2-32–0

ClpP

Decreasing the growth rate of the transplanted OCI-AML2 cell line

[365]

ACS-010759 and ME-344

electron transport chain

Inhibit oxidative phosphorylation (OXPHOS)

[366]

DON (6-diazo-5-oxo-l-norleucine)

enzymes that utilize Gln as substrate

Gln antagonists

[367]

BPTES, compound 968 and CB-839

Glutaminase

Investigated in vitro, in vivo and in different clinical trials

[368]

1) BCT-100

2) ADI-PEG 20

Arginine production

1) Recombinant arginase

2) mycoplasma-derived arginine deiminase

[369]

Etomoxir

CPT1

Resensitizing resistant LSCs to venetoclax with azacitidine (ven/aza) therapy

[370]

Avocatin B

FAO

Enhancing glucose and FA absorption

[371]

Signaling factors related drugs/inhibitors

Vorolanib (CM082)

tyrosine kinase receptor

Inhibiting the proliferation of human umbilical vein endothelial cells (HUVECs) and the formation of HUVEC tubes in vitro and several xenograft models

[372]

Curcumin

VEGF

Stronger anti-apoptosis effect in combination of thalidomide as a VEGF inhibitor in KG-1 and U937 cell lines

[373]

Selenium-L-methionine (SLM)

VEGFR

Stronger anti-cancer effect in combination of Bevacuzimab

[374]

HuMV833, SU5416, SU6668, SU11248, ZD6474 and PTK787/ZK222584 (Vatalanib), VEGF-Trap and AngiozymeTM

VEGF

Anti-angiogenesis agents against VEGF of VEGFR in several cancer therapy

[322]

Apatinib

expression of VEGFR2 and Its downstream signaling cascades, such as PI3K, MAPK, and STAT3 pathways

Inhibiting cell proliferation, reducing the capacity of colony-forming, and inducing apoptosis and cell cycle arrest in AML cells in combination of HHT

[375]

Shikonin, Polyphyllin I (PPI), Astragalin heptacetate (AHA), Hinesol and Parthenolide (PLT)

JNK

-

[328]

RXC004 and CWP232291

CBP/β-catenin

Act as CBP/β-catenin antagonist

[376]

SM04755

WNT

Act as anti-WNT signaling agent

[377]

Glasdegib

Hh pathway

Interacting with smoothened protein and inhibiting the growth of AML cell lines and human leukemia stem cells

[378]

Immune checkpoint related drugs/inhibitirs

Cytosine arabinoside (cytarabine)

CD80 and CD86

Inducing the expression of CD80 and CD86 and reducing the expression of PD-1 on leukemic cells, making them more susceptible to cytotoxic T-lymphocyte-mediated killing

[379]

Ipilimumab

CTLA-4

Anti-CTLA-4 monoclonal antibody

[380]

Pembrolizumab, nivolumab, and cemiplimab

PD-1

Anti-PD-1 antibodies

[381]

Atezolizumab, avelumab, and durvalumab

PD-L1

Anti-PD-L1 antibodies

[382]

TSR-022 and MBG453

TIM-3

Anti-TIM-3 monoclonal antibodies

NCT02817633

NCT02608268

Daratumumab and Isatuximab

CD38

Anti-CD38 antibodies

[158]

Poliovirus-Rhinovirus Chimera (PVSRIPO)

CD155

An oncolytic viral therapy

[383]

OMP-313M32, BMS-986207, MTIG7192A and MTIG7192A

TIGIT

Their alone or combination effects with nivolumab and atezolizumab have been clinically investigated

[384]

TTI-CD200

CD200

an anti-CD200 antibody investigated on leukemia-propagating cells (LPCs) and mice models

[233]