Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule

Zhao, Qiancheng; Lan, Tianlong; Su, Shang; Rao, Yu

doi:10.1039/c8cc07813k

Cited by 127 publications

(89 citation statements)

References 39 publications

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“… 18 , 19 Targets that have been shown to be degraded by PROTACs include members of bromodomain-containing proteins such as the BET proteins (Brd2, Brd3 and Brd4), 7 , 8 , 9 , 14 , 15 , 17 , 20 , 21 amongst other epigenetic protein classes; 22 , 23 , 24 , 25 , 26 protein kinases; 10 , 12 , 27 , 28 , 29 , 30 , 31 as well as non-bromodomain and non-kinase target proteins. 32 , 33 , 34 , 35 Recent progress in understanding principles of PROTAC mode of action, and demonstration of applicability across different target classes, suggest that PROTACs have the potential to target new protein families, including proteins that are difficult to block using current approaches. Clinical validation of small molecules inducing protein degradation is provided by recent discoveries on the molecular mechanism of thalidomide and related clinical anticancer immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which induce the proteasomal-dependent degradation of cancer-driving proteins.…”

Section: Introductionmentioning

confidence: 99%

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Girardini

Maniaci

Hughes

et al. 2019

Bioorganic & Medicinal Chemistry

100

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Section: Introductionmentioning

confidence: 99%

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Girardini

Maniaci

Hughes

et al. 2019

Bioorganic & Medicinal Chemistry

100

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“…In 2018, the Yu Rao group published the first PARP1-targeting PROTAC (compound 60) by connecting the PARP1 inhibitor niraparib and the MDM2 ligand nutlin-3 283 (Fig. 32).…”

Section: Parp1mentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

Self Cite

406

414

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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“…While this research was underway, Yu Rao and co-workers successfully disclosed the first PARP-1 degrader based on a niraparib derivative which induces PARP-1 cleavage and cell apoptosis in the MDA-MB-231 cell line 33 . Here, we chose colorectal adenocarcinoma SW620 cell line that highly expressed PARP-1 14 to prove the suitability of our olaparib-based PROTAC 1-3 for chemically induced PARP-1 degradation.…”

Section: Evaluation Of the Degradation Profile On Parpp-1mentioning

confidence: 99%

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

Zhang

Chang

Zhang

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

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Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule

Abstract: We report for the first time a PARP1-targeting PROTAC small molecule to selectively induce the cleavage of PARP1.

Cited by 127 publications

References 39 publications

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs

PROTACs: great opportunities for academia and industry

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

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