Discovery of a Novel, Selective and Irreversible Inhibitor (Abivertinib) of Mutated EGFR and T790M-induced Resistance for the Treatment of NSCLC

Mao, Long; Tang, Wei; Zhang, Xiaoying; Liu, Jia; Chen, Yile; Yang, Hua; Weng, Bojie; Mo, Xiaopeng; Bao, Yi-Mei; Teng, Li; Xu, Lijun; Zhang, Yuren; Wu, Jian; Zhou, Guanglin; Liang, Bin; Xu, Changxu; Xi, Biao; Zhao, Li; Xu, Rongda; Fang, Carol; Xu, Wanhong; Wang, Xiaobo; Xu, Xiao

doi:10.1016/j.medidd.2020.100035

Cited by 8 publications

(6 citation statements)

References 36 publications

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“…A phase 2 trial of the patients with EGFR T790Mþ has completed accrual, and a phase 3 trial "REZOR" comparing rezivertinib to gefitinib has commenced (Table 1). 33 Abivertinib also inhibits cellular proliferation of HCC827 cell line at IC 50 of 4 nM and A-431 cell line at IC 50 of 645 nM. 33 The RP2D of abivertinib was determined to be 300 mg twice daily although MTD was not reached in the phase 1 study in which 52 patients were enrolled.…”

Section: Rezivertinib (Bpi-7711)mentioning

confidence: 99%

“…33 Abivertinib also inhibits cellular proliferation of HCC827 cell line at IC 50 of 4 nM and A-431 cell line at IC 50 of 645 nM. 33 The RP2D of abivertinib was determined to be 300 mg twice daily although MTD was not reached in the phase 1 study in which 52 patients were enrolled. Doselimiting toxicities were grade 3 ALT or AST elevation.…”

Section: Rezivertinib (Bpi-7711)mentioning

confidence: 99%

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Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Nagasaka

Zhu

Lim

et al. 2021

Journal of Thoracic Oncology

136

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Single-agent osimertinib is the standard of care for the firstline treatment of advancedEGFRþ NSCLC and remained the only marketed third-generation EGFR tyrosine kinase inhibitor (TKI) until March 2020 when almonertinib (HS-10296) was approved in the People's Republic of China for the treatment of advanced EGFR T790Mþ NSCLC based on a phase 2 expansion study of a phase 1/2 trial. In this review, we profiled many of the third-generation EGFR TKIs in latestage clinical development (e.g., almonertinib, lazertinib, alflutinib 1 , rezivertinib, ASK120069, SH-1028, D-0316, and abivertinib) based on their interim results from phase 1 and phase 2 trials, and included the designs of the phase 3 trials and their chemical structures when publicly available. We also listed other third-generation EGFR TKIs in pipeline development based on the search of clinical trial registration websites. In addition, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, mavelertinib), including phase 3 results of rociletinib and naquotinib. We further profiled combination clinical trial design of the thirdgeneration EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704), and ACROSS2 (NCT04500717) that if positive can potentially usher in the next standard of care for advanced EGFRþ NSCLC.

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Section: Rezivertinib (Bpi-7711)mentioning

confidence: 99%

Section: Rezivertinib (Bpi-7711)mentioning

confidence: 99%

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Nagasaka

Zhu

Lim

et al. 2021

Journal of Thoracic Oncology

136

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“…Abivertinib, developed by Zhejiang ACEA Pharmaceutical Co., Ltd., has applied for listing to treat non-small cell lung cancer (NSCLC) in China. Abivertinib is a specific inhibitor of tyrosine kinases that targets mutant forms of human EGFR and BTK [49]. Abivertinib has been investigated for its potential use in the management of NSCLC and B-cell malignancies.…”

Section: Abivertinib (Ac-0010)mentioning

confidence: 99%

A Comprehensive Review of Small-Molecule Inhibitors Targeting Bruton Tyrosine Kinase: Synthetic Approaches and Clinical Applications

Zhang,

Wen,

Zhao

et al. 2023

Molecules

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Bruton tyrosine kinase (BTK) is an essential enzyme in the signaling pathway of the B-cell receptor (BCR) and is vital for the growth and activation of B-cells. Dysfunction of BTK has been linked to different types of B-cell cancers, autoimmune conditions, and inflammatory ailments. Therefore, focusing on BTK has become a hopeful approach in the field of therapeutics. Small-molecule inhibitors of BTK have been developed to selectively inhibit its activity and disrupt B-cell signaling pathways. These inhibitors bind to the active site of BTK and prevent its phosphorylation, leading to the inhibition of downstream signaling cascades. Regulatory authorities have granted approval to treat B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with multiple small-molecule BTK inhibitors. This review offers a comprehensive analysis of the synthesis and clinical application of conventional small-molecule BTK inhibitors at various clinical stages, as well as presents promising prospects for the advancement of new small-molecule BTK inhibitors.

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“…A class of pyrrolopyrimidine‐based heterocyclic small molecules 22a – 22m (Mao et al, 2020) were designed and synthesized as third‐generation EGFR inhibitors. Among them, compound 22d exhibited excellent inhibitory activity against H1975 and HCC827cells, with IC 50 values of 8.3 and 4.0 nM, respectively, and had good selectivity against EGFR L858R/T790M with IC 50 value of 0.18 nM.…”

Section: Pyrrole‐fused Heterocyclic Derivatives Being Used As Egfr Ki...mentioning

confidence: 99%

Pyrrole‐based EGFR inhibitors for the treatment of NCSLC: Binding modes and SARs investigations

Luo

et al. 2022

Chem Biol Drug Des

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The treatment of advanced non‐small cell lung cancer (NSCLC) has made substantial progress due to the rapid development of small molecule targeted therapy, with dramatically prolonged survival. As an effective drug for the treatment of NSCLC, epidermal growth factor receptor (EGFR) inhibitors are currently experiencing issues like severe adverse events and drug resistance. It is urgent to develop novel types of EGFR inhibitors to overcome the abovementioned limitations. Pyrrole always works well as a probe for the creation of novel medication candidates for hard‐to‐treat conditions like lung cancer. Although the design, synthesis, and biological assays of pyrrole derivatives have been reported, their inhibitory actions against the receptor tyrosine kinase (RTK) EGFR have not been in‐depthly studied. This review highlights the small molecule EGFR inhibitors containing pyrrole heterocyclic pharmacophores in recent years, and the research on their mechanism, biological activity, and structure–activity relationship (SAR).

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Discovery of a Novel, Selective and Irreversible Inhibitor (Abivertinib) of Mutated EGFR and T790M-induced Resistance for the Treatment of NSCLC

Cited by 8 publications

References 36 publications

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

A Comprehensive Review of Small-Molecule Inhibitors Targeting Bruton Tyrosine Kinase: Synthetic Approaches and Clinical Applications

Pyrrole‐based EGFR inhibitors for the treatment of NCSLC: Binding modes and SARs investigations

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