Table 4 Therapeutic approaches against ATR and ATM in hematologic malignancies

ATM

KU-55933

Jurkat cells

Impairment of the auto-phosphorylation of ATM and inhibition of H2AX phosphorylation

[203, 225]

MV4-11 cells (AML cell line)

ATM inhibition radiosensitized MV4-11 leukemia cells

[182]

P39 and MOLM-13 cell lines (MDS cell lines)

ATM inhibition increase radiosensitization of MDS cells

[182]

EBV-driven Burkitt lymphoma cells

Inhibition of EBV replication through inhibition of KAP1 phosphorylation

[205]

Ramos cells

Prevention of ATM auto-phosphorylation and potentiation of etoposide-induced apoptosis

[226]

Cisplatin-resistant MCL cell line (JeKo-1/DDP)

Enhanced cisplatin-induced DNA damage

[206]

HCL cell line MLMA

Induction of apoptosis through inhibiting NF-κB pathway

[207]

KU-59403

Jurkat cells

Showing higher potency, tissue distribution, and efficacy over KU-55933

[225]

AZD0156

AML

exhibits therapeutic potential in a mouse model of MLL-rearranged AML

[227]

KU-60019

Human B cell lymphoma cell lines, lymphoblastoid cell lines, and myeloma lines

KU-60019 potentiates bendamustine activity

[212]

MCL cell lines

KU60019 synergizes the antineoplastic effect of romidepsin

[228]

Caffeine

(Inhibitor of both ATM and ATR)

K562 leukemia cells

Caffeine sensitises the cells to

genotoxic modalities, particularly irradiation

[229]

Lymphoma patients

Potentiated chemotherapy and induction of complete remission

[213]

ATR

VE-821

APL cells

Increase of radio sensitization

[217, 218]

MM cells

Significantly increased apoptosis of MM cells in combination with KU-55933

[218]

TP53-mutant MM cell lines

As monotherapy alone and in combination with DNA damaging agents, CX5461 or melphalan

[230]

VE-822 (VX-970)

AML

Increase antileukemic activity of hydroxyurea and gemcitabine in AML mouse model

[220]

AZD6738

CLL patients

ATR inhibition induces synthetic lethality in TP53- or ATM-defective CLL cells

[221]

ATM-deficient DLBCL model

Combination therapy with carboplatin, bendamustine, and cyclophosphamide

[219]

Relapsed/refractory high-risk CLL patients

A phase I clinical trial of AZD6738 in combination with acalabrutinib

[Trial identifier: NCT03328273]

-

BAY1895344

MCL models

Synergistic anti-tumor activity in combination with DNA damage-inducing chemotherapy or radiation therapy

[224]

AZ20

AML-MLL murine model

Strong cytotoxic effects in vitro and in murine models, irrespective of p53 status

[231]

WO2010/073034

ATM-deficient MCL

Promising results both in vitro and in vivo models

[223]