Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors

Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro . The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC 50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC 50 = 0.090 μM) was equal to that of Foretinib (IC 50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure–activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.

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“… 3 , 4 Prevention of c-Met overexpression is a potentially effective method for treating cancers related to c-Met abnormal activation. 5 − 7 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

et al. 2020

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“…The (S)-methyl group may act as conformational restriction, which is important for the positioning of the benzene ring. This explains how the resulting compounds significantly decreased potency in the cellular assay when the (S)-methyl group was replaced by a (R)-methyl group (75) or the ethyl group on the nitrogen atom was removed (76). 126 To the best of our knowledge, a multitargeted kinase MET/SRC/ CSF1R inhibitor, TPX-0022 (elzovantinib, structure undisclosed) developed by Turning Point Therapeutics, has entered phase I/II (NCT03993873).…”

Section: Small Molecule Inhibitors Of Metmentioning

confidence: 99%

“…74 This may be due to the smaller C−S−C angle preventing 2,6-dichloro-3-fluorobenzyl from adopting a proper position for π−π stacking and the change in the overall properties of the inhibitor. When the 2-aminopyridine core was replaced by a bicyclic ring system harboring different linkers such as sulfur (22), 75 sulfone (23), 75 cyclopropyl (24), 75 and sulfonamide (25), 76 or the benzyloxy linker was replaced with a rigid amide (26), 77 all of them displayed less potency than that of crizotinib. SMU-B (27), bearing a different hydrophilic group showed comparable MET kinase inhibitory activity to crizotinib.…”

Section: Small Molecule Inhibitors Of Metmentioning

confidence: 99%

Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy

Wang

2023

J. Med. Chem.

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MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.

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“…Further optimization of c‐Met kinase inhibitors 35 and 37 was performed to improve protein‐binder interactions at regions of the binding site near the solvent front, resulting in the identification of compounds 36 and 38 , respectively …”

Section: Exploitation Of Solvent‐exposed Regions For Structure‐based mentioning

confidence: 99%

“…GRK2, G protein-coupled receptor kinase [Color figure can be viewed at wileyonlinelibrary.com] Further optimization of c-Met kinase inhibitors 35 and 37 was performed to improve protein-binder interactions at regions of the binding site near the solvent front, resulting in the identification of compounds 36 and 38, respectively. 47,48 Similarly, further optimization at position(s) within existing scaffolds (39 and 41) that orient toward the solvent without specific hydrogen bond formation resulted in the discovery of selective PI3K inhibitors (40 and 42). 49,50 (A) (B) F I G U R E 9 Optimization of peripheral substituents for the solvent-exposed regions of kinases, affording advanced inhibitors.…”

mentioning

confidence: 99%

Molecular design opportunities presented by solvent‐exposed regions of target proteins

Jiang

Zhou

et al. 2019

Medicinal Research Reviews

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Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.

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Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1 H -pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors

Cited by 11 publications

References 29 publications

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy

Molecular design opportunities presented by solvent‐exposed regions of target proteins

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