Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Chen, Wenteng; Guo, Xiao; Zhang, Can; Ke, Di; Zhang, Guolin; Yu, Yongping

doi:10.1016/j.ejmech.2019.111734

Cited by 12 publications

(4 citation statements)

References 42 publications

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“…Second and third ALK-TKIs play different roles in inhibiting secondary mutations in the treatment of drug resistance related to the use of other ALK-TKIs (12). ALK kinase domain mutations were noted in 66.7% of patients after treatment with crizotinib, and mutations that confer resistance, including G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V, were investigated (16) The L1196M mutation is located in the protein kinase domain of the ALK protein (UniProt.org: Q9UM73) and similarly demonstrated to be a resistance mutation in the crizotinib-resistant patient in our report. However, optimal sequential administration of ALK inhibitors after resistance to crizotinib in patients harboring the L1196M missense mutation has not been elucidated, especially patients with brain metastasis.…”

Section: Discussionmentioning

confidence: 99%

A rare KIF5B-ALK fusion variant in a lung adenocarcinoma patient who responded to crizotinib and acquired the ALK L1196M mutation after resistance: a case report

Zeng¹,

Liu²,

Wang³

et al. 2021

Ann Palliat Med

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An increasing number of anaplastic lymphoma kinase (ALK) gene fusion variants have been reported with the popularity of next-generation sequencing (NGS), such as striatin gene (STRN)-ALK, EMAP like 4 (EML4)-ALK and S1 RNA binding domain 1 (SRBD1)-ALK. The clinical outcomes of nonsmall cell lung cancer (NSCLC) patients improved dramatically with the treatment of tyrosine kinase inhibitors (TKIs), but responses to ALK-TKIs differ even for the same fusion variants with different breakpoints. The clinical effectiveness of ALK-TKIs on a new fusion variant needs to be evaluated. Here, we report a case of a lung adenocarcinoma patient, a 70-year-old nonsmoking Chinese man, with rare ALK rearrangement form of, namely, a kinesin family member 5B (KIF5B)-ALK (K20:A20) fusion which was identified in tissue by capture-based NGS. The patient achieved a partial response (PR) after treatment with crizotinib. Additionally, an ALK L1196M mutation was detected when the disease progressed after 11 months and was indicated to be sensitive to ceritinib. As far as we know, this is the first report showing that KIF5B-ALK (K20:A20) is a fusion variant that is sensitive to crizotinib. We provided a treatment strategy for managing NSCLC patients with KIF5B-ALK (K20:A20) fusion or ALK L1196M mutation after crizotinib resistance. Additionally, dynamic genomic analysis of ALK-TKIs treatments is important.

show abstract

Section: Discussionmentioning

confidence: 99%

A rare KIF5B-ALK fusion variant in a lung adenocarcinoma patient who responded to crizotinib and acquired the ALK L1196M mutation after resistance: a case report

Zeng¹,

Liu²,

Wang³

et al. 2021

Ann Palliat Med

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“…Thus, having excellent potency in neuronal nitric oxide synthase (nNOS) inhibition and significant low P-glycoprotein and breast cancer resistant-protein substrate. [43] Related compounds showed also inhibition of non-structural protein 5B (NS5B), which is a viral RNA-dependent RNA polymerase, with improved safety profile. [44]…”

Section: Chemistryselectmentioning

confidence: 99%

Physico‐Chemical Properties, Pharmacokinetics, Molecular Docking and In‐Vitro Pharmacological Study of a Cobalt (II) Complex Based on 2‐Aminopyridine

et al. 2022

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The organic‐inorganic hybrid compound (2‐HAP)2[CoBr4], (2‐HAP=2‐protonated aminopyridinium cation) was characterized by various physicochemical techniques. Hirshfeld surfaces and 2D fingerprint plots reveal the intermolecular interactions accountable for the generation of the crystal packing. The differential scanning calorimetric (DSC) disclosed three phase transitions at T1=61.9 °C, T2=107.6 °C and T3=172 °C. The electronic parameters such as frontier molecular orbitals, HOMO‐LUMO energy and electrochemical band gaps (E’g) were computed. The redox properties of the complex were examined by cyclic voltammetry. The thermodynamic properties of the compound were computed for the range temperature of 100–1000 K. The antioxidant activities were examined using DPPH, ABTS, β‐carotene and FRAP assays. The anticancer effects were evaluated using malignant Mat−Ly−Lu and Walker 256/B cell lines. The antiviral effects of the organic part of the hybrid compound were tested using molecular docking; interestingly, the binding predicted energy was −4.0 vs −5.3 kcal/mol, for chloroquine as a reference. The drug‐likeness, pharmacokinetics, molecular binding and chemo‐preventive assays show that (2‐HAMP)2[CoBr4] has promising biological potentials.

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“…Several Ba/F3 lines exogenously expressing genetic fusions such as CD74-ROS1, TPM3-ROS1 or SDC4-ROS1 have been established. They have been of great importance in pre-clinical studies to demonstrate the in vitro efficacy of crizotinib, entrectinib, cabozantinib or lorlatinib [34,[41][42][43].…”

Section: Ba/f3 Cellsmentioning

confidence: 99%

Pre-clinical modelling of ROS1+ non-small cell lung cancer

Terrones¹,

Beeck²,

Camp³

et al. 2023

Lung Cancer

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Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Cited by 12 publications

References 42 publications

A rare KIF5B-ALK fusion variant in a lung adenocarcinoma patient who responded to crizotinib and acquired the ALK L1196M mutation after resistance: a case report

A rare KIF5B-ALK fusion variant in a lung adenocarcinoma patient who responded to crizotinib and acquired the ALK L1196M mutation after resistance: a case report

Physico‐Chemical Properties, Pharmacokinetics, Molecular Docking and In‐Vitro Pharmacological Study of a Cobalt (II) Complex Based on 2‐Aminopyridine

Pre-clinical modelling of ROS1+ non-small cell lung cancer

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