Design, synthesis, and molecular docking studies of novel pomalidomide-based PROTACs as potential anti-cancer agents targeting EGFR<sup>WT</sup> and EGFR<sup>T790M</sup>

Aboelez, Moustafa O.; Belal, Amany; Xiang, Guangya; Ma, Xiang

doi:10.1080/14756366.2022.2062338

Cited by 19 publications

(12 citation statements)

References 53 publications

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“…The designed compounds have been docked against the ATP-binding sites of wild-type EGFR-TK (EGFR WT , PDB:4HJO) [82] and mutant EGFR-TK (EGFR T790M , PDB: 3W2O) with MOE (Figure 6) [83]. On the basis of in vitro results (Figure 6), compound 16 displays higher EGFR degradation efficacy than the other six compounds, through forming two hydrogen bonds with the Arg779 and Lys721 amino acids, thereby binding EGFR WT , and two hydrogen bonds with the Ser720 and Lys745 amino acids, thereby binding EGFR T790M ; these findings support the key role of molecular docking in PROTAC screening [84].…”

Section: Protac Drugs Based On Small Molecules Discovered By Molecula...supporting

confidence: 57%

Computational strategies for PROTAC drug discovery

Wang

Leung

2023

Acta Materia Medica

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Proteolysis-targeting chimeras (PROTACs), a novel targeted protein degradation technology for potential clinical drug discovery, is composed of a protein-targeting ligand covalently linked to an E3 ligase ligand. Through recruiting E3 ligase to target proteins, PROTACs elicit ubiquitination and subsequent degradation of targets via the ubiquitin-proteasome system. In the past few decades, molecular docking and virtual screening have emerged as an efficient strategy in drug discovery for identifying compounds from a large database of chemical structures. For PROTACs, molecular docking accurately simulates the protein-PROTAC-E3 ternary complex, thus greatly accelerating structure-activity-relationship analysis, and improving ligand affinity and selectivity. In this review, we summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery. To date, approximately nine target proteins and twelve PROTACs have been successfully developed through molecular docking and virtual screening. Finally, the potential challenges of molecular docking and virtual screening-based PROTACs are discussed.

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Section: Protac Drugs Based On Small Molecules Discovered By Molecula...supporting

confidence: 57%

Computational strategies for PROTAC drug discovery

Wang

Leung

2023

Acta Materia Medica

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“…A generic docking operation was initiated at the ligand’s location, utilizing the prepared database and all of the previously specified software parameters. − Finally, the best pose was selected for each compound to be further investigated according to the obtained scores, binding mode similarity, and RMSD values. − …”

Section: Methodsmentioning

confidence: 99%

“… 54 − 56 Finally, the best pose was selected for each compound to be further investigated according to the obtained scores, binding mode similarity, and RMSD values. 57 − 59 …”

Section: Methodsmentioning

confidence: 99%

Thieno[2,3-b]thiophene Derivatives as Potential EGFR^WT and EGFRT^790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies

et al. 2022

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Microwave-assisted synthesis and spectral analysis of certain novel derivatives of 3,4-diaminothieno[2,3-b]thiophene-2,5-dicarbonitrile 1–7 were carried out. Compounds 1–7 were examined for cytotoxicity against MCF-7 and A549 cell lines using the quantitative MTT method, and gefitinib and erlotinib were used as reference standards. Compounds 1–7 were shown to be more active than erlotinib against the two cell lines tested. Compound 2 outperformed regular erlotinib by 4.42- and 4.12-fold in MCF-7 and A549 cells, respectively. The most cytotoxic compounds were subsequently studied for their suppression of kinase activity using the homogeneous time-resolved fluorescence assay versus epidermal growth factor receptor (EGFRWT) and EGFR790M. With IC50 values of 0.28 ± 0.03 and 5.02 ± 0.19, compound 2 was demonstrated to be the most effective against both forms of EGFR. Furthermore, compound 2 also had the best antioxidant property, decreasing the radical scavenging activity by 78%. Molecular docking research, on the other hand, was carried out for the analyzed candidates (1–7) to study their mechanism of action as EGFR inhibitors. In silico absorption, distribution, metabolism, excretion, and toxicity tests were also performed to explain the physicochemical features of the examined derivatives.

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“…It also exerted a good degradation effect (DC 50 = 32.9 nM) in A549 cells, and maximum degradation occurred at 72 h (D max = 96%). 165 Taking into consideration promising degradation activity of different CRBN-based EGFR-PROTACs, a group of eight CRBN-based PROTACs was assessed for EGFR L858R/T790M degradation. A preliminary molecular docking-guided design strategy resulted in 43 which degraded EGFR L858R/T790M (DC 50 = 13.2 nM) and inhibited the NCI-H1957 cell proliferation (IC 50 = 46.82 nM).…”

Section: Advancements In the Development Of Protacs Targeting The Egfrmentioning

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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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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Design, synthesis, and molecular docking studies of novel pomalidomide-based PROTACs as potential anti-cancer agents targeting EGFR^WT and EGFR^T790M

Cited by 19 publications

References 53 publications

Computational strategies for PROTAC drug discovery

Computational strategies for PROTAC drug discovery

Thieno[2,3-b]thiophene Derivatives as Potential EGFR^WT and EGFRT^790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies

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

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Design, synthesis, and molecular docking studies of novel pomalidomide-based PROTACs as potential anti-cancer agents targeting EGFRWT and EGFRT790M

Cited by 19 publications

References 53 publications

Computational strategies for PROTAC drug discovery

Computational strategies for PROTAC drug discovery

Thieno[2,3-b]thiophene Derivatives as Potential EGFRWT and EGFRT790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies

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

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Design, synthesis, and molecular docking studies of novel pomalidomide-based PROTACs as potential anti-cancer agents targeting EGFR^WT and EGFR^T790M

Thieno[2,3-b]thiophene Derivatives as Potential EGFR^WT and EGFRT^790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies