Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo

Zhang, Wenjuan; Li, Pengyun; Sun, Shiyang; Jia, Changkai; Yang, Ning; Zhuang, Xiaomei; Zheng, Zhibing; Wang, Jintao

doi:10.1016/j.ejmech.2022.114509

Cited by 18 publications

(9 citation statements)

References 24 publications

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“…Further, 43 showed a better in vivo pharmacokinetic profile and plasma protein binding (99.8%) than 6 (98.67%). 166 It was also concluded that the antiproliferative activity decreases with the increasing linker length of the degrader molecules which have 6 as the EGFR ligand and 12 as a CRBN ligand (Figure 10B).…”

Section: Advancements In the Development Of Protacs Targeting The Egfrmentioning

confidence: 96%

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: 96%

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

et al. 2023

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“…Li and the colleagues (Zhang et al., 2022) selected an osimertinib derivative 7 m (Yang et al., 2022), which is a potent antitumor activity and high selectivity against EGFR L858R/T790M as the ligand and lenalidomide was selected as the ligand of CRBN. The representative compounds 13a ( 22 ) and 13b ( 23 ) inhibited NCI–H1975 cell proliferation with IC 50 values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 μM against A549 or H1299 cells, whose selectivity was more than 1700‐fold.…”

Section: Egfr Protacsmentioning

confidence: 99%

EGFR degraders in non‐small‐cell lung cancer: Breakthrough and unresolved issue

Shen,

Chen,

Liu

et al. 2024

Chem Biol Drug Des

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The epidermal growth factor receptor (EGFR) has been well validated as a therapeutic target for anticancer drug discovery. Osimertinib has become the first globally accessible third‐generation EGFR inhibitor, representing one of the most advanced developments in non‐small‐cell lung cancer (NSCLC) therapy. However, a tertiary Cys797 to Ser797 (C797S) point mutation has hampered osimertinib treatment in patients with advanced EGFR‐mutated NSCLC. Several classes of fourth‐generation EGFR inhibitors were consequently discovered with the aim of overcoming the EGFRC797S mutation‐mediated resistance. However, no clinical efficacy data of the fourth‐generation EGFR inhibitors were reported to date, and EGFRC797S mutation‐mediated resistance remains an “unmet clinical need.” Proteolysis‐targeting chimeric molecules (PROTACs) obtained from EGFR‐TKIs have been developed to target drug resistance EGFR in NSCLC. Some PROTACs are from nature products. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR‐targeting degraders along with its advantages and outstanding challenges.

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“… 28 13a;13b Osimertinib CRBN ligand L858R/T790M LUAD In vitro ; In vivo H1975 xenograft Zhang et al. 29 CFT8919 EGFR allosteric inhibitor (not disclosed) CRBN ligand L858R; L858R/C797S; L858R/T790M; L858R/T790M/C797S LUAD In vitro ; In vivo H1975 xenograft C4 Therapeutics 30 KRAS XY-4-88 ARS-1620 CRBN ligand GFP-KRAS LUAD In vitro NT Zeng et al. 31 LC-2 MRTX849 VHL ligand KRAS G12C LUAD In vitro NT Bond et al.…”

Section: Progress In the Protac Development For Lung Cancer Treatmentmentioning

confidence: 99%

“…Inspired by this exciting study, multiple groups have developed several novel EGFR PROTACs, with some showing in vivo antitumor efficacy in preclinical models. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 79 For example, the Zhang group recently reported an orally bioavailable EGFR PROTAC, HJM-561, as a promising therapeutic strategy for overcoming EGFR triple mutation-mediated drug resistance in NSCLC, because it specifically degraded EGFR mutant proteins and induced potent antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models that were resistant to osimertinib treatment. 27 In another study, 28 the Zhu group generated novel potent covalent inhibitor dacomitinib-based EGFR degraders and identified a promising compound, 13, which potently induced degradation of EGFR(Del19) with low nanomolar DC(50) value in HCC827 cells, but not other EGFR mutant, wild-type EGFR proteins or HER2 and HER4 receptors from the EGFR family.…”

Section: Progress In the Protac Development For Lung Cancer Treatmentmentioning

confidence: 99%

PROTAC therapy as a new targeted therapy for lung cancer

Zheng

Kaye

et al. 2023

Molecular Therapy

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Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo

Cited by 18 publications

References 24 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

EGFR degraders in non‐small‐cell lung cancer: Breakthrough and unresolved issue

PROTAC therapy as a new targeted therapy for lung cancer

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