Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

Fang, Feifei; Dai, Yang; Wang, Hao; Ji, Yinchun; Liang, Xuewu; Peng, Xia; Li, Jiyuan; Zhao, Yangrong; Li, Chunpu; Wang, Danyi; Li, Yazhou; Zhang, Dong; Zhang, Dan; Geng, Meiyu; Liu, Hong; Ai, Jing; Zhou, Yu

doi:10.1016/j.apsb.2023.10.002

Cited by 4 publications

(2 citation statements)

References 67 publications

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“…Blocking or the ablation of AXL has the potential to restore drug-sensitivity, which provides new combination strategies against EGFR/HER-expressing tumors [ 61 ]. The development of AXL-targeted inhibitors is dynamic [ 62 , 63 , 64 , 65 , 66 ]. Although there are promising clinical trials and studies targeting AXL [ 67 , 68 ], redundancy of signaling through other TAM (TYRO3, AXL, and MERTK) family kinases may decrease their effectiveness [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Ujlaky-Nagy,

Szöllősi,

Vereb

2024

IJMS

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Pertuzumab (Perjeta®), a humanized antibody binding to the dimerization arm of HER2 (Human epidermal growth factor receptor-2), has failed as a monotherapy agent in HER2 overexpressing malignancies. Since the molecular interaction of HER2 with ligand-bound EGFR (epidermal growth factor receptor) has been implied in mitogenic signaling and malignant proliferation, we hypothesized that this interaction, rather than HER2 expression and oligomerization alone, could be a potential molecular target and predictor of the efficacy of pertuzumab treatment. Therefore, we investigated static and dynamic interactions between HER2 and EGFR molecules upon EGF stimulus in the presence and absence of pertuzumab in HER2+ EGFR+ SK-BR-3 breast tumor cells using Förster resonance energy transfer (FRET) microscopy and fluorescence correlation and cross-correlation spectroscopy (FCS/FCCS). The consequential activation of signaling and changes in cell proliferation were measured by Western blotting and MTT assay. The autocorrelation functions of HER2 diffusion were best fitted by a three-component model corrected for triplet formation, and among these components the slowly diffusing membrane component revealed aggregation induced by EGFR ligand binding, as evidenced by photon-counting histograms and co-diffusing fractions. This aggregation has efficiently been prevented by pertuzumab treatment, which also inhibited the post-stimulus interaction of EGFR and HER2, as monitored by changes in FRET efficiency. Overall, the data demonstrated that pertuzumab, by hindering post-stimulus interaction between EGFR and HER2, inhibits EGFR-evoked HER2 aggregation and phosphorylation and leads to a dose-dependent decrease in cell proliferation, particularly when higher amounts of EGF are present. Consequently, we propose that EGFR expression on HER2-positive tumors could be taken into consideration as a potential biomarker when predicting the outcome of pertuzumab treatment.

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Section: Discussionmentioning

confidence: 99%

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Ujlaky-Nagy,

Szöllősi,

Vereb

2024

IJMS

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“…Several multitargeting MET inhibitors have shown strong inhibitory abilities against MER and AXL, including glesatinib ( 5 ), cabozantinib ( 6 ), and others with nanomolar-level IC 50 values (Figure ). − Notably, merestinib (LY2801653, 7 ) and tamnorzatinib (ONO-7475, 8 ), identified as highly potent dual MER/AXL inhibitors, also behaved strong inhibitory abilities against MET protein. , In addition to the aforementioned clinical candidates, numerous MER-selective, AXL-selective, or dual MER/AXL inhibitors are currently under study at various stages of development. − …”

Section: Introductionmentioning

confidence: 99%

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment

Li,

Lai,

Kuo

et al. 2024

J. Med. Chem.

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A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1Hpyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8 + T-cells, and helper CD4 + T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

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Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

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Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

Cited by 4 publications

References 67 publications

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

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