Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer

Wang, Junwei; He, Guangchao; Li, Hui; Ge, Yiran; Wang, Shuping; Xu, Yungen; Zhu, Qihua

doi:10.1016/j.ejmech.2020.113054

Cited by 25 publications

(12 citation statements)

References 33 publications

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“…Moreover, ZSTK474 decreased BRCA1/2 expression, which might be attributed to the activation of ETS transcription factors that are involved in ERK-dependent BRCA1/2 downregulation [28]. Since Ibrahim and Juvekar et al for the first time reported that blockage of PI3K/Akt pathway could result in HR deficiency by reducing BRCA1/2 expression and Rad51 foci formation in breast cancer [28,47], a number of clinical trials and preclinical research combining PI3K inhibitors with PARP inhibitors were performed on HR proficient cancers [48][49][50][51]. Therefore, as a PI3K inhibitor, ZSTK474 has potential to be used as a sensitizer in combination with DNA-damaging treatments, including chemotherapy agents and radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

Jiao

Zhu

Shao

et al. 2022

BioMed Research International

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is used as the standard chemotherapeutic agent for GBM but with limited success, and treatment failure is mainly due to tumor resistance. One of the leading causes of TMZ resistance is the upregulation of the DNA repair mechanism. Therefore, targeting the DNA damage response (DDR) is proposed to be an effective strategy to sensitize tumor cells to TMZ. In the present study, we demonstrated that the combined use of the PI3K inhibitor ZSTK474 and TMZ showed synergetic anticancer effects on human GBM cells in vitro and in vivo. The combination treatment led to significantly increased cell apoptosis and DNA double strand breaks (DSBs). In addition, a mechanistic study indicated that TMZ enhanced the homologous recombination (HR) repair efficiency in GBM cells, while ZSTK474 impaired HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51, thereby sensitizing GBM cells to TMZ. Moreover, TMZ activated the PI3K signaling pathway through upregulation of the PI3K catalytic subunits p110α and p110β and the phosphorylation of Akt. Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM.

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Section: Discussionmentioning

confidence: 99%

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

Jiao

Zhu

Shao

et al. 2022

BioMed Research International

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“…Compared with PARPi, PARP/PI3K dual inhibitor has excellent anti-proliferation properties on TNBC cells. In addition, PARP/PI3K dual inhibitors showed good metabolic stability and high safety [108]. Both PARP and histone deacetylase (HDAC) are important antitumor targets.…”

Section: Combination Strategiesmentioning

confidence: 99%

PARP in colorectal cancer: Molecular mechanisms, immunity, clinical trials, and drug combinations

Wu¹,

Wei²,

Deng³

et al. 2023

neo

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The changes in cell homeostasis in the tumor microenvironment may affect the development of colorectal cancer (CRC). Genomic instability is an important factor. Persistent genomic instability leads to epigenetic changes, and mutations are a major factor in the progression of CRC. Based on these mechanisms, it is reasonable to link poly (ADP-ribose) polymerase (PARP) with the treatment of colorectal cancer. PARP is mainly involved in DNA repair, which has an essential role in the DNA damage response and prevention of DNA damage, and maintains oxidation and superoxide redox homeostasis in the intracellular environment of the tumor. This article reviews the latest research progress on PARP and PARP inhibitors (PARPi) in CRC. It mainly includes molecular mechanisms, immunity, clinical trials, and combination strategies of CRC. The research of PARPi in CRC has broad prospects, and the combinations with other drugs are the main research direction in the future.

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“…Then, an attempt was made to replace the phthalazine moiety of 78 with a smaller pharmacophore benzofuran-7-carboxamide . The resulting compound 79 showed effective and balanced PI3Kα and PARP-1 inhibitory activities.…”

Section: Rational Design Of Multitargeted Ligandsmentioning

confidence: 99%

“…174 Then, an attempt was made to replace the phthalazine moiety of 78 with a smaller pharmacophore benzofuran-7carboxamide. 178 The resulting compound 79 showed effective and balanced PI3Kα and PARP-1 inhibitory activities. On the basis of compounds 78 and 79, Wang et al replaced the ATP domain binding groups with the corresponding pharmacophore of GDC-0980, a potent PI3Kα inhibitor in phase-II clinical research.…”

Section: Rational Design Of Multitargeted Ligandsmentioning

confidence: 99%

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Liu

et al. 2021

J. Med. Chem.

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The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the design strategy of incorporating the second activity into an existing single-active ligand. If the binding sites of both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with similar functional groups. If the binding sites are large or adjacent to the solution, two key pharmacophores can be fused directly. If the binding regions are small and deep inside the proteins, the linkedpharmacophore strategy might be the only way. The added pharmacophores of second targets should not affect the binding mode of the original ones. Moreover, the inhibitory activities of the two targets need to be adjusted to achieve an optimal ratio.

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Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer

Cited by 25 publications

References 33 publications

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

PARP in colorectal cancer: Molecular mechanisms, immunity, clinical trials, and drug combinations

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

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