Design and discovery of 4-anilinoquinazoline ureas as multikinase inhibitors targeting BRAF, VEGFR-2 and EGFR

Zhang, Qingwen; Diao, Yuan-Yuan; Wang, Fei; Fu, Ying; Tang, Fei; You, Qidong; Hou-yuan, Zhou

doi:10.1039/c3md00096f

Cited by 25 publications

(9 citation statements)

References 26 publications

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“…Among them, compound 111 (Figure ) exhibited significant potency toward BRAF, BRAF V600E, EGFR, and VEGFR-2. Docking studies showed that the compound might nicely fit the DFG-out conformation of BRAF …”

Section: Recent Design Of Urea Derivatives In Drug Discoverymentioning

confidence: 99%

“…Docking studies showed that the compound might nicely fit the DFG-out conformation of BRAF. 207 Further modification on the aryl group resulted in diaryl ureas (112) as dual EGFR and VEGFR-2 inhibitors. The SAR studies established that a terminal diaryl urea moiety with a chlorine atom at the ortho-position of the urea group was optimal for high inhibitory potency.…”

Section: Recent Design Of Urea Derivatives In Drug Discoverymentioning

confidence: 99%

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Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

2019

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The urea functionality is inherent to numerous bioactive compounds, including a variety of clinically approved therapies. Urea containing compounds are increasingly used in medicinal chemistry and drug design in order to establish key drug−target interactions and fine-tune crucial drug-like properties. In this perspective, we highlight physicochemical and conformational properties of urea derivatives. We provide outlines of traditional reagents and chemical procedures for the preparation of ureas. Also, we discuss newly developed methodologies mainly aimed at overcoming safety issues associated with traditional synthesis. Finally, we provide a broad overview of urea-based medicinally relevant compounds, ranging from approved drugs to recent medicinal chemistry developments.

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Section: Recent Design Of Urea Derivatives In Drug Discoverymentioning

confidence: 99%

Section: Recent Design Of Urea Derivatives In Drug Discoverymentioning

confidence: 99%

Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

2019

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“…Several molecules have been reported to show nonselective dual inhibition against both B-Raf and EGFR kinases. 38,39 However, to the best of our knowledge, there is rarely a successful report on the treatment of intrinsic resistant colorectal cancers by using a B-Raf/EGFR dual inhibitor.…”

Section: ■ Introductionmentioning

confidence: 99%

Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

Cheng

Chang²,

Zhang

et al. 2014

J. Med. Chem.

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Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.

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“…We have worked on the design, synthesis, and evaluation of small molecule kinase inhibitors for years (11). Herein, we report on a privileged pharmacophores-based hybriddesign approach to identify novel type II BRAF inhibitors.…”

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confidence: 99%

Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

et al. 2013

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V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF.

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Design and discovery of 4-anilinoquinazoline ureas as multikinase inhibitors targeting BRAF, VEGFR-2 and EGFR

Cited by 25 publications

References 26 publications

Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

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