Skip to main content

Table 3 Pre-clinical studies on PARP1 and DNA-PK inhibitors against hematologic malignancies

From: Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

Target

Inhibitors

Type of malignancy

Highlights

Ref

PARP1

Olaparib (AZD2281, MK-7339)

MCL and MLL-AF9 rearranged Leukemia cells

Higher sensitivity of double-deficient ATM/p53 MCL cells, compared to mono-deficient MCL cells in ATM

[106]

AG14361

MCL cells

Enhanced topotecan-induced apoptosis independent of TP53 status

[151]

PJ-34

Patient-derived ATLL cells

p53-mediated caspase 3-dependent apoptosis

[155]

HL60, MOLT4, and K562 human leukemia cell lines

Synergistic effect in combination with histone deacetylase inhibitor, vorinostat

[156]

BMN-673 (talazoparib)

Patient-derived CLL samples

Inhibited the proliferation of CLL cells independently of p53/ATM function

[158]

Primary AML samples AML mouse models

Enhanced apoptosis in combination with decitabine

[166]

Veliparib (ABT-888)

Patients with relapsed/refractory lymphoma and MM

Enhances the cytotoxicity of bendamustine and rituximab

[161]

MM cells

MM xenografts in SCID mice

Combined treatment with CDK inhibitor dinaciclib resulted in synthetic lethality of MM cells

[162]

Acute leukemia, high-risk MPNs

Promising results in Combined treatment with topotecan and carboplatin in phase I study

[164]

P10

Human leukemic cell line Nalm6

Induction of G2/M arrest and accumulation of DNA damage

[168]

DNA-PK

Wortmannin

Human leukemia cells

Sonolisib (PX-866) is Irreversible wortmannin analogue

PWT-458 is PEGylated derivative of wortmannin

[193, 194]

NU7026

Primary CLL cells

Synergistic effects with chlorambucil

[195]

CC-115

CLL, NHL, and MM

Phase I clinical trial

A dual inhibitor of DNA-PK and mTOR

[177, 196]

IC86621

NHL and HL

Synergistic effects with bleomycin and etoposide

[183]

CC-122 (Avadomide)

NHL and MM

Phase I clinical trial

[178, 197]

NU7441

Pre-B ALL cells

Increase of chemosensitivity to doxorubicin

[198]

OK-1035

L5178Y cells (lymphoma cell line)

Preclinical testing

[199]

Dbait (AsiDNA or DT01)

Lymphoma and leukemia cells

32 bp double-stranded DNA fragment that mimics DNA lesion and traps DNA repair enzymes

A dual inhibitor of DNA-PK and PARP1

[191]

GRN163L (Imetelstat)

CLL

Imetelstat sensitizes primary CLL lymphocytes to fludarabine

A dual inhibitor of DNA-PK and telomerase

[192]