Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Zhan, Zhengsheng; Ai, Jing; Liu, Qiufeng; Ji, Yinchun; Chen, Tiantian; Xu, Yechun; Geng, Meiyu; Duan, Wenhu

doi:10.1021/ml500066m

Cited by 37 publications

(21 citation statements)

References 19 publications

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“…1‐((4‐Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.146 g, 0.654 mmol), HATU (0.415 g, 1.09 mmol), and DMF (5 mL) were placed in a round‐bottom flask, and then added DIPEA (0.26 mL, 1.49 mmol). Aniline 3 (0.157 g, 0.53 mmol) dissolved in DMF (5 mL) was added after 10 minutes.…”

Section: Methodsmentioning

confidence: 99%

One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met

Lien

Klaveness

Olberg

2017

Labelled Comp Radiopharmac

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Cabozantinib is an FDA-approved kinase inhibitor for the treatment of medullary thyroid cancer and advanced renal cell carcinoma, which exerts its therapeutic effect by inhibiting, among others, the tyrosine kinase c-Met. Noninvasive imaging techniques are becoming increasingly important clinically to ensure drug efficacy, staging, monitoring, and patient stratification. PET isotope labelled tyrosine kinase inhibitors have, for the same reason, potential as PET tracers for imaging of various cancers. On the basis of cabozantinib, we synthesized the novel boronic acid pinacol ester 4 as a labelling precursor, where the boronic ester moiety replaces the fluorine native to this kinase inhibitor. By this, we wanted to explore whether recently developed Cu-mediated fluorination methods are adaptable to more complex substrates and thereby provide easy access to [18 F]cabozantinib directly.Hydrolysis was implemented before preparative purification due to challenges with on-column hydrolysis of the precursor 4, and [ 18 F]cabozantinib was obtained in ≥99% radiochemical purity and in 2.8 ± 0.05% (n = 4) isolated decay corrected yield in a synthesis time of 90 minutes. The molar activity of representative batches was determined to be 17 ± 8 GBq/μmol.

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Section: Methodsmentioning

confidence: 99%

One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met

Lien

Klaveness

Olberg

2017

Labelled Comp Radiopharmac

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“…The same trend is also seen with the trifluorinated compound 18d performing overall better in the cell‐based assay than compounds 14a and 15a , despite its lower c‐Met affinity. This observation is in compliance with known SAR on related structures that have shown that c‐Met affinity is more sensitive to modifications on the terminal benzene ring than is VEGFR . Compared with cabozantinib, higher growth suppressive effects are seen with 15b and 18b in several of the cell lines, particularly in cells derived from leukemia, CNS, and breast cancer.…”

Section: Resultsmentioning

confidence: 99%

“…The combined basic extracts were then acidified to pH 1–2 with HCl (1 M), and the title compound was achieved by suction filtration as a white solid (0.41 g, 41%). 1 H NMR (400 MHz, DMSO‐ d 6 ): δ 10.71 (s, 1H), 7.60–7.57 (m, 2H), 7.15–7.10 (m, 2H), 1.39 (s, 4H) …”

Section: Methodsmentioning

confidence: 99%

Design, synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitors

Lien

Pettersen

Haugen

et al. 2019

Archiv der Pharmazie

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Based on the cabozantinib scaffold, novel c-Met inhibitors were rationalized from the limited knowledge of structure-activity relationships for the quinoline 6-position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c-Met active site. In addition, ortho-fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c-Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6-position, while the ortho-fluorinations performed were shown to give considerable reductions in the c-Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the para-amino substituted 15b and 18b.

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“…The multitarget c-Met kinase inhibitor binds to the inactive conformation of the kinase and belongs to the type II c-Met kinase inhibitor 12,13 , which binds to not only c-Met but also VEGFR, FGFR, ALK, EGFR, MAT1R. All these studies suggest that simultaneous inhibition of the two tyrosine kinase receptors results in better anti-tumour effects 14,15 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

Liang

Wang

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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C-Met plays a crucial role in the development and progression of neoplastic disease. Type II c-Met inhibitors recognise the inactive DFG-out conformation of the kinase, result in better anti-tumour effects due to synergistic effect against the other kinases. According to our previous works, an (E)-N'-benzylidene group was selected as the initial fragment. Two series of (E)-N'-benzylidene hydrazides were designed by fragment growth method. The inhibitory activities were in vitro investigated against c-Met and VEGFR-2. Compound 10b exhibited the most potent inhibitory activity against the c-Met inhibitor (IC 50 ¼ 0.37 nM). Compound 11b exhibited multi-target c-Met kinase inhibitory activity as a potential type II c-Met inhibitor (IC 50 ¼ 3.41 nM against c-Met; 25.34 nM against VEGFR-2). The two compounds also demonstrate the feasibility of fragment-based virtual screening method for drug discovery. ARTICLE HISTORY

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Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Cited by 37 publications

References 19 publications

One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met

One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met

Design, synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitors

Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

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Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Cited by 37 publications

References 19 publications

One‐step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c‐Met

One‐step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c‐Met

Design, synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitors

Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

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One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met

One‐step synthesis of [¹⁸F]cabozantinib for use in positron emission tomography imaging of c‐Met