Recent Developments of RET Protein Kinase Inhibitors With Diverse Scaffolds As Hinge Binders

Jia, Congcong; Chen, Wang; Feng, Zijian; Liu, Zhaopeng

doi:10.4155/fmc-2020-0170

Cited by 12 publications

(11 citation statements)

References 50 publications

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“…There are no high-resolution or cocrystal structures of PIKfyve. Our own kinase inhibitor design experience and work of others in the field have confirmed the aminopyrimidine as a common hinge-binding motif. − Although they involve an unrelated human protein kinase that shares only 21% sequence identity with PIKfyve, recently solved cocrystal structures of AMG28 bound to TTBK1 (PDB: 7JXX and 7ZHN) demonstrate that the aminopyrimidine ring in AMG28 makes essential hydrogen bonds with the hinge of TTBK1. , These studies suggest that aminopyrimidine could also bind the hinge of PIKfyve. It was suggested by the authors of the Biogen TTBK1 paper that the three methylene groups of the seven-membered ring help maintain the planarity of the molecule rather than making key contacts with the protein .…”

Section: Resultsmentioning

confidence: 81%

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

et al. 2022

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From a designed library of indolyl pyrimidinamines, we identified a highly potent and cell-active chemical probe (17) that inhibits phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). Comprehensive evaluation of inhibitor selectivity confirmed that this PIKfyve probe demonstrates excellent kinome-wide selectivity. A structurally related indolyl pyrimidinamine (30) was characterized as a negative control that lacks PIKfyve inhibitory activity and exhibits exquisite selectivity when profiled broadly. Chemical probe 17 disrupts multiple phases of the lifecycle of β-coronaviruses: viral replication and viral entry. The diverse antiviral roles of PIKfyve have not been previously probed comprehensively in a single study or using the same compound set. Our scaffold is a distinct chemotype that lacks the canonical morpholine hinge-binder of classical lipid kinase inhibitors and has a non-overlapping kinase off-target profile with known PIKfyve inhibitors. Our chemical probe set can be used by the community to further characterize the role of PIKfyve in virology.

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Section: Resultsmentioning

confidence: 81%

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

et al. 2022

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“…In addition, one more hydrogen bond was found between the pyridine ring of pralsetinib and SER811 of RET. The literature evidence also highlights the contribution of residues in the binding pocket of RET [ 44 ]. On analyzing the binding pattern of LF1, one hydrogen bond was found between the hydroxy group of LF1 and ALA807 residue of the protein.…”

Section: Resultsmentioning

confidence: 99%

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

Ramesh

Shanthi

2022

Molecules

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Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies.

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“…The most frequent partners occur in KIF5B and CCD6, which represent around 60% and 20% of cases, respectively [137]. Different therapeutic medications targeting RET fusions have been developed, and, to date, selpercatinib and pralsetinib medications are proposed while waiting for marketing approval by the FDA and EMA [140][141][142][143][144][145]. However, testing for these fusions will now become systematic at diagnosis for all patients presenting with advanced-stage NS-NSCLC, knowing that patients with RET fusions do not generally respond well to immune checkpoint inhibitors (ICIs) [146][147][148][149].…”

Section: Biomarkers Just Beyond the "Big Five" In 2021 221 Ret Fusionsmentioning

confidence: 99%

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

Hofman

2021

JMP

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The discovery and clinical validation of biomarkers predictive of the response of non-squamous non-small-cell lung carcinomas (NS-NSCLC) to therapeutic strategies continue to provide new data. The evaluation of novel treatments is based on molecular analyses aimed at determining their efficacy. These tests are increasing in number, but the tissue specimens are smaller and smaller and/or can have few tumor cells. Indeed, in addition to tissue samples, complementary cytological and/or blood samples can also give access to these biomarkers. To date, it is recommended and necessary to look for the status of five genomic molecular biomarkers (EGFR, ALK, ROS1, BRAFV600, NTRK) and of a protein biomarker (PD-L1). However, the short- and more or less long-term emergence of new targeted treatments of genomic alterations on RET and MET, but also on others’ genomic alteration, notably on KRAS, HER2, NRG1, SMARCA4, and NUT, have made cellular and blood samples essential for molecular testing. The aim of this review is to present the interest in using cytological and/or liquid biopsies as complementary biological material, or as an alternative to tissue specimens, for detection at diagnosis of new predictive biomarkers of NS-NSCLC.

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Recent Developments of RET Protein Kinase Inhibitors With Diverse Scaffolds As Hinge Binders

Cited by 12 publications

References 50 publications

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

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