Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686

Li, Qinlan; Guo, Qian; Wang, Shuyi; Wan, Shanhe; Li, Zhonghuang; Zhang, Jiajie; Wu, Xia

doi:10.1016/j.ejmech.2022.114455

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…An amide linker containing 40a showed the best degradation activity in H1975 cell lines (DC 50 = 355.9 nM), and it also induced apoptosis and arrested the cell cycle at the G0/G1 phase. 164 Moreover, a series of seven pomalidomide-based PROTACs showed good anti-EGFR activity at low concentrations in different cancer cell lines. Among these, 41 with EGFR -TKI D (42) showed better EGFR inhibitory activity with IC 50 values of 0.10 μM and 4.02 μM than 2 (IC 50 = 0.32 μM) and 1 (IC 50 = 21.44 μM) in EGFR WT and EGFR T790M , respectively.…”

Section: Advancements In the Development Of Protacs Targeting The Egfrmentioning

confidence: 99%

“…Further, a promising in vitro result was observed in the MTT assay of PROTAC having pomalidomide rather than the modified pomalidomide-based PROTACs. An amide linker containing 40a showed the best degradation activity in H1975 cell lines (DC 50 = 355.9 nM), and it also induced apoptosis and arrested the cell cycle at the G0/G1 phase …”

Section: Egfr Protacs As a Novel Therapeutic Modalitymentioning

confidence: 99%

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Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

et al. 2023

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Epidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality.

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Section: Advancements In the Development Of Protacs Targeting The Egfrmentioning

confidence: 99%

Section: Egfr Protacs As a Novel Therapeutic Modalitymentioning

confidence: 99%

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

et al. 2023

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“…13b) based on an irreversible EGFR inhibitor canertinib was reported (Qu et al 2021), which selectively degrades mutated EGFR L858R/T790M proteins in H1975 cells, and EGFR del19 protein in PC-9 cells but not EGFR WT in A549 cells (Qu et al 2021). Recently, Li et al (2022) discovered EGFR L858R/T790M degraders based on CO-1686. PROTAC 1q were selectively and effectively inhibited EGFR del19 mutation in PC-9 and EGFR L858R/T790M in H1975 cells (DC 50 value of 355.9 nM), while did not affect EGFR WT expression in A549 cells.…”

Section: Protac: a Hope For The Egfr Targeted Therapiesmentioning

confidence: 99%

“…PROTAC 1q were selectively and effectively inhibited EGFR del19 mutation in PC‐9 and EGFR L858R/T790M in H1975 cells (DC 50 value of 355.9 nM), while did not affect EGFR WT expression in A549 cells. Furthermore, PROTAC 1q were significantly induce the apoptosis of H1975 cells and arrest the cell cycle in G 0 /G 1 phase (Li et al 2022). Although, no PROTACs were reported to degrade EGFR C797S until date, the emergence of more EGFR TKIs potentiates the development of new PROTAC family that can target the triple mutation EGFR L858R/T790M,/C797S and other resistant cells.…”

Section: Fasn and Egfr Inhibitors: Therapeutic Intervention For Cancermentioning

confidence: 99%

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Role of EGFR and FASN in breast cancer progression

Chaturvedi,

Biswas,

Sadhukhan

et al. 2023

J. Cell Commun. Signal.

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Breast cancer (BC) emerged as one of the life-threatening diseases among females. Despite notable improvements made in cancer detection and treatment worldwide, according to GLOBACAN 2020, BC is the fifth leading cancer, with an estimated 1 in 6 cancer deaths, in a majority of countries. However, the exact cause that leads to BC progression still needs to be determined. Here, we reviewed the role of two novel biomarkers responsible for 50-70% of BC progression. The first one is epidermal growth factor receptor (EGFR) which belongs to the ErbB tyrosine kinases family, signalling pathways associated with it play a significant role in regulating cell proliferation and division. Another one is fatty acid synthase (FASN), a key enzyme responsible for the de novo lipid synthesis required for cancer cell development. This review presents a rationale for the EGFR-mediated pathways, their interaction with FASN, communion of these two biomarkers with BC, and improvements to overcome drug resistance caused by them.

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Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Zhang,

Xie,

Ran

et al. 2024

Journal Cellular Physiology

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Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch‐activated PROTACs, offering precise targeting of previously “undruggable” proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.

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Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686

Cited by 16 publications

References 35 publications

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

Role of EGFR and FASN in breast cancer progression

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

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