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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.

ABSTRACT: A new class of EGFR PROTACs based on pomalidomide was developed, synthesised, and tested for their cytotoxic activity against a panel of human cancer cells. Compounds 15-21 were showed to be more effective against the four tested cell lines than erlotinib. In particular, compound 16 was found to be the most potent counterpart as it was 5.55, 4.34, 5.04, and 7.18 times more active than erlotinib against MCF-7, HepG-2, HCT-116, and A549 cells, respectively. Compound 15 was revealed to be more active than doxorubicin against the four tested cell lines. Furthermore, the most potent cytotoxic compounds were studied further for their kinase inhibitory effects against EGFR^WT and EGFR^T790M using HTRF test. Compound 16 showed to be the most effective against both kinds of EGFR, with IC₅₀ values of 0.10 and 4.02 µM, respectively. Compound 16 could effectively degrade EGFR protein through ubiquitination (D_max = 96%) at 72 h in the tested cells.

SUBMITTER: O Aboelez M

PROVIDER: S-EPMC9067978 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

O Aboelez Moustafa M Belal Amany A Xiang Guangya G Ma Xiang X

Journal of enzyme inhibition and medicinal chemistry 20221201 1

A new class of EGFR PROTACs based on pomalidomide was developed, synthesised, and tested for their cytotoxic activity against a panel of human cancer cells. Compounds 15-21 were showed to be more effective against the four tested cell lines than erlotinib. In particular, compound 16 was found to be the most potent counterpart as it was 5.55, 4.34, 5.04, and 7.18 times more active than erlotinib against MCF-7, HepG-2, HCT-116, and A549 cells, respectively. Compound 15 ...[more]

PMID: 35470756

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Project description:A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFRWT and EGFRT790M protein kinases, with IC50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFRWT and EGFRT790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFRWT and EGFRT790M, with binding scores of -6.40 kcal mol-1 and -7.53 kcal mol-1, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol-1, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFRWT and EGFRT790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.

Dataset Information

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

Publications

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>.

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