The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations

Xia, Zhenqiang; Huang, Ridong; Zhou, Xinglong; Chai, Yingying; Chen, Hai; Ma, Lingling; Yu, Quanwei; Liu, Ying; Liu, Weimin; He, Yang

doi:10.1016/j.ejmech.2021.113711

Cited by 20 publications

(5 citation statements)

References 58 publications

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“…We collected 30 papers published in recent years, which focus on small-molecule inhibitors of EGFR L858R/T790M/C797S triple mutations and compiled a data set containing 221 valuable active structures and their corresponding kinase inhibitory activities (expressed as IC 50 ). − For screening efficiency, only structures with IC 50 < 5 μM and with accurate numerical representation have been retained in the collation. The activity values were converted to the pIC 50 (−log 10 (IC 50 )) for the sake of the same magnitude on our data.…”

Section: Materials and Methodsmentioning

confidence: 99%

Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors

Chang,

Zhang,

Tian

et al. 2024

ACS Omega

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Epidermal growth factor receptor (EGFR) plays a pivotal regulatory role in treating patients with advanced nonsmall cell lung cancer (NSCLC). Following the emergence of the EGFR tertiary CIS C797S mutation, all types of inhibitors lose their inhibitory activity, necessitating the urgent development of new inhibitors. Computer systems employ machine learning methods to process substantial volumes of data and construct models that enable more accurate predictions of the outcomes of new inputs. The purpose of this article is to uncover innovative fourth-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with the aid of machine learning techniques. The paper's data set was high-dimensional and sparse, encompassing both structured and unstructured descriptors. To address this considerable challenge, we introduced a fusion framework to select critical molecule descriptors by integrating the full quadratic effect model and the Lasso model. Based on structural descriptors obtained from the full quadratic effect model, we conceived and synthesized a variety of small-molecule inhibitors. These inhibitors demonstrated potent inhibitory effects on the two mutated kinases L858R/T790M/C797S and Del19/T790M/C797S. Moreover, we applied our model to virtual screening, successfully identifying four hit compounds. We have evaluated these hit ADME characteristics and look forward to conducting activity evaluations on them in the future to discover a new generation of EGFR-TKI.

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Section: Materials and Methodsmentioning

confidence: 99%

Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors

Chang,

Zhang,

Tian

et al. 2024

ACS Omega

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“…The docking analysis revealed that compound 30 a and ChemistrySelect avitinib share comparable docking features around both the Michael acceptor and pharmacophore regions. [98] Othman and colleagues developed the pyrimidine and pyrazole hybrids as EGFR inhibitors. The MCF-7 and HCC cells were subjected to the evaluate the cytotoxicity of reported compounds.…”

Section: Chemistryselectmentioning

confidence: 99%

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

Pal¹,

Teli²,

Matada³

et al. 2023

ChemistrySelect

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proved to be the magical weapon in designed and discovery of synthetic molecules as they acquired comprehensive range of pharmacological properties. In recent year (2018-2022) Nheterocyclic derivatives were uncovered as the potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed the limitations of currently accessible drugs by consecrating, anatomy, mutation of EGFR, and its role in different types of cancer. The review highlights the medicinal chemistry prospective emphasising about the designing strategies, docking studies, biological evaluation, selectivity and structural activity relationship of N-heterocyclic compounds. Our review will support the medicinal chemists in direction for the development of novel N-heterocyclic based EGFR TKIs.

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“…NSCLC accounts for approximately 84% of all lung cancers; approximately 75% of NSCLC patients are in the middle and advanced stages when diagnosed with metastatic symptoms, and the 5 year survival rate is relatively low. , Therefore, the design and development of anticancer drugs targeting EGFR offer broad therapeutic prospects for the treatment of NSCLC and other cancers . Current inhibitory strategies against EGFR mainly involve the design of small-molecule tyrosine kinase inhibitors (TKIs), which replace ATP in the kinase domain and inhibit the phosphorylation of EGFR and downstream cascades. − …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antitumor Activity of Potent and Selective EGFR L858R/T790M Inhibitors and Identification of a Combination Therapy to Overcome Acquired Resistance in Models of Non-small-cell Lung Cancer

Pei

Wang

et al. 2023

J. Med. Chem.

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Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for the treatment of non-small-cell lung cancer (NSCLC). Here, we report the identification, structure optimization, and structure–activity relationship studies of quinazoline derivatives as novel selective EGFR L858R/T790M inhibitors. The most promising compound, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC50 = 3.5 nM) and greater than 368-fold selectivity over EGFR WT (IC50 = 1290 nM), a 6.7-fold improvement over osimertinib. Furthermore, 28f effectively inhibited downstream signaling pathways and induced apoptosis in mutant cells. In the H1975 xenograft in vivo model, 28f exhibited a good tumor suppressive effect. Furthermore, the combination of 28f with the ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy with 28f in 28f-resistant cells and in vivo. In conclusion,28f could become a candidate drug for the treatment of NSCLC, and the combination of 28f and dasatinib is expected to overcome EGFR resistance.

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The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations

Cited by 20 publications

References 58 publications

Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors

Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

Design, Synthesis, and Antitumor Activity of Potent and Selective EGFR L858R/T790M Inhibitors and Identification of a Combination Therapy to Overcome Acquired Resistance in Models of Non-small-cell Lung Cancer

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