Identification of TRE‐130 as Reversible Inhibitor of Pan‐EGFR Mutants while Sparing EGFR Wild‐Type Activity

Duggirala, Krishna Babu; Choe, Hyeonjeong; Jeon, Byeong Uk; Jung, Mina; Go, Areum; Lim, Bogyu; Park, Chaewon; Yoon, Jiyeun; Chae, Chong Hak; Cho, Byoung Chul; Choi, Gildon; Lee, Kwang-Ho

doi:10.1002/bkcs.11886

Cited by 2 publications

(3 citation statements)

References 20 publications

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“…In other words, EGFR is a transmembrane protein that plays a pivotal role in angiogenesis, cell signaling, and cell proliferation mechanisms [11]. Therefore, inhibition of the EGFR receptor leads to a cellular imbalance that may cause disturbance in the differentiation, proliferation, and growth of cancer cells [12]. Overexpression of EGFR has been reported in 60% of lung cancer patients, 58% of large cell carcinoma patients, 43% of breast cancer patients, 39% of adenocarcinoma patients, 38% of squamous cell carcinoma patients, and to some extent in prostate, colon, urinary bladder, melanoma, kidney, nasopharynx, leukemia, pancreas, and thyroid cancer cells [13].…”

Section: ■ Introductionmentioning

confidence: 99%

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Kurniawan,

Yudha,

Nugraha

et al. 2024

Indones. J. Chem.

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Epidermal growth factor receptor (EGFR) is found to be overexpressed in cancer cells as it controls angiogenesis, cell signaling, and proliferation mechanisms. Therefore, EGFR has been known as a common target for the initial screening of new anticancer agents. Either xanthone or chalcone has been evaluated as the anticancer agents, and their activity strongly depends on the type and position of the attached functional group. Therefore, molecular hybridization between xanthone and chalcone could yield novel anticancer agents through the EGFR inhibition mechanism. Herein, a series of xanthone-chalcone derivatives with hydrogen-bond-acceptor or hydrogen-bond-donor substituents at ortho, meta, and para positions was evaluated as the EGFR inhibitor. Thirty-seven xanthone-chalcones were designed and docked in the active site of EGFR. Compared to the native ligand, pristine xanthone-chalcone gave a 1.215× stronger binding energy and a 13.97× lower binding constant. Compound 3SH was found to be the most promising candidate due to its strongest binding energy (−9.71 kcal/mol) and the lowest binding constant (0.08 µM). Furthermore, molecular dynamic studies demonstrated that complex EGFR-3SH was stable for 100 ns simulation. These in silico investigations show that the xanthone-chalcone derivative is a promising novel anticancer agent to be examined through in vitro and in vivo assays.

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Section: ■ Introductionmentioning

confidence: 99%

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Kurniawan,

Yudha,

Nugraha

et al. 2024

Indones. J. Chem.

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“…Brigatinib ( 1 ), first developed as an ALK inhibitor, also inhibited the Del19/T790M/C797S-mutated EGFR-expressing Ba/F3 cell growth with an IC 50 value of 55.5 nM . With the replacement of the dimethylphosphine oxide (DMPO) of 1 with sulfonamide, Lee et al developed a new series of compounds (e.g., TRE-069 ( 2 )) showing good selectivity toward the EGFR C797S mutant over the wild-type EGFR . We thus hypothesized that incorporating such type of small-molecule inhibitors into the PROTACs may result in selective degradation of the EGFR Del19/T790M/C797S mutant while sparing the wild-type EGFR.…”

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confidence: 99%

“…The most potent compound 4 obtained a DC 50 value of 5.9 nM with a VHL ligand as the E3 ligase recruiter. 19 On the basis of the predicted binding mode of 2 in EGFR, 25 we proposed that the solvent-exposed piperidine moiety of 2 could be the best position for linking to the E3 ligase ligand. Accordingly, a set of potential EGFR PROTACs were thus designed and synthesized by joining 2 or the brigatinib analog 3 to the VHL ligand (5) with different linkers (Figure 1).…”

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confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

Zhang

Xie

Ai-Furas

et al. 2022

ACS Med. Chem. Lett.

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The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFRDel19/T790M/C797S mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC50 of 8 nM. It also showed good antiproliferation activity (IC50 = 0.02 μM) against Ba/F3-EGFRDel19/T790M/C797S cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.

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Identification of TRE‐130 as Reversible Inhibitor of Pan‐EGFR Mutants while Sparing EGFR Wild‐Type Activity

Cited by 2 publications

References 20 publications

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

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