ArticleAngewandte Chemie (International ed. in English)2015
Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.
Article in Angewandte Chemie (International ed. in English), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 41 citations in OpenAlex.
- Synthesis, and evaluation of novel low nanomolar isoindigo-based RET kinase inhibitors.RSC advances · 2026Article
- Discovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins.Scientific reports · 2025Article
- Article
- Analysis of Pz-1, a promising therapeutic for organophosphorus poisoning from rodent plasma by liquid chromatography-tandem mass spectrometry.Journal of pharmaceutical and biomedical analysis · 2025Article
- Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors.Bioorganic & medicinal chemistry · 2024Article
- De novo generation of multi-target compounds using deep generative chemistry.Nature communications · 2024Article
- Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy.Journal of hematology & oncology · 2022Review
- Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose.Journal of medicinal chemistry · 2022Article
- Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor.European journal of medicinal chemistry · 2021Article
- Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development.Journal of medicinal chemistry · 2021Review
- Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases.Scientific reports · 2021Article
- Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered by a Fragment Optimization Approach.ChemMedChem · 2021Article
- The importance of the RET gene in thyroid cancer and therapeutic implications.Nature reviews. Endocrinology · 2021Review
- Review
- Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.European journal of medicinal chemistry · 2020Article
- Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology.Journal of medicinal chemistry · 2020Article
- Synthesis of Constrained Heterocycles Employing Two Post-Ugi Cyclization Methods for Rapid Library Generation with In Cellulo Activity.ChemistrySelect · 2017Article
- Polypharmacology-based ceritinib repurposing using integrated functional proteomics.Nature chemical biology · 2017Article
- Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.Science translational medicine · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a type II tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg(-1) day(-1) per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0 mg kg(-1), which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.