Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

Lin, Songwen; Wang, Chunyang; Ji, Ming; Wu, Dongping; Lv, Yuanhao; Zhang, Kehui; Dong, Yunhui; Jin, Jing; Chen, Jiajing; Zhang, Jingbo; Li, Sheng; Li, Yan; Chen, Xiaoguang; Xu, Heng

doi:10.1021/acs.jmedchem.8b00416

Cited by 33 publications

(30 citation statements)

References 39 publications

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“…For example, despite a 2–3 fold drop in potency compared with that of 2,4-difluorophenyl sulfonamide, 2-chloro-4-florophenyl sulfonamide ( 19b ), or 5-chlorothiophene-2-sulfonamide ( 19c ) showed high inhibitory activity with an IC 50 of 4.6 nM and 8.0 nM, respectively. This activity was attributed to the fact that the electron-deficient aryl group resulted in a more acidic sulfonamide NH proton being able to make a stronger charged interaction with Lys802 in PI3Kα [ 24 ]. Consistent with this finding, when 2,4-difluorophenyl was replaced with methyl ( 19d ), the PI3Kα inhibitory potency dropped over 10-fold (IC 50 = 53 nM).…”

Section: Resultsmentioning

confidence: 99%

“…Acetic acid, 1,4-dioxane, acetonitrile and dried THF were purchased from domestic corporations and used without further purification. Aryl borates were synthesized according to our previous work [ 24 ]. Nuclear magnetic resonance spectroscopy ( 1 H NMR and 13 C NMR) was performed on Bruker Advance 400M NMR spectrometers, and high-resolution LC-MS was carried out by Agilent LC/MSD TOF.…”

Section: Methodsmentioning

confidence: 99%

“…The kinase inhibitory activity assay was performed by Shanghai ChemPartner Co., Ltd. (Shanghai, China). For details, see our previously published protocols [ 24 ]. Molecular docking study was conducted in the Schrodinger software.…”

Section: Methodsmentioning

confidence: 99%

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Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Xia

Zhang

et al. 2020

Molecules

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A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Xia

Zhang

et al. 2020

Molecules

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“…To identify novel PI3K/HDAC dual inhibitors, Zhang and colleagues focused on the use of quinazoline‐based PI3K inhibitors ( 17 ), which interact at the hinge through the N3 of the quinazoline ring [83] . It is possible to explore modifications at position 8.…”

Section: General Multitarget Hdac and Pi3k Inhibitorsmentioning

confidence: 99%

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

2020

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The discovery of histone deacetylase (HDAC) inhibitors is a hot topic in the medicinal chemistry community regarding cancer research. This is related primarily to two factors: success in the clinic, e. g., the four FDA‐approved HDAC inhibitors, and strong versatility to combine their pharmacophoric features to design new hybrid compounds with multitarget profiles. Thus, the selection of adequate pharmacophores to combine, i. e., combining targets that can result in a synergistic effect, is desirable, as it increases the probability of discovering a new useful therapeutic strategy. In this work, we highlight the design of multitarget HDAC/PI3K inhibitors. Although this approach is still in its early stages, many significant works have described the design and pharmacological evaluation of this new promising class of multitarget inhibitors, where compound CUDC‐907, which is already in clinical trials, stands out. Therefore, the question emerges of whether there still space for the design and evaluation of new multitarget HDAC/PI3K inhibitors. When considering the selectivity profile of the described multitarget compounds, the answer appears to be in the affirmative, especially since the first examples of compounds with a certain selectivity profile only recently appeared in 2020.

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“…XH30 is a PI3K inhibitor that can cross the blood-brain barrier (Lin et al, 2018). XH30 has previously been demonstrated to have robust antitumor activity in GBM and brain metastases of lung cancer in vivo (Lin et al, 2018;Ji et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Zhang

Lin

et al. 2021

Front. Pharmacol.

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Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

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Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

Cited by 33 publications

References 39 publications

Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

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