ArticleProceedings of the National Academy of Sciences of the United States of America2023
A biophysical framework for double-drugging kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
- A design approach for bitopic kinase inhibitors.Nature · 2026Article
- Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.American journal of medical genetics. Part A · 2026Article
- Bend and Snap: Computationally Exploring the Helix Bias for Classifying Abl Kinase Allosteric Modulators.Journal of chemical information and modeling · 2026Article
- Substrate-Derived Peptides for Selective Covalent Inhibition of Protein Tyrosine Kinases.ACS chemical biology · 2026Article
- Substrate-derived peptides for selective covalent inhibition of protein tyrosine kinases.bioRxiv : the preprint server for biology · 2026Article
- Uncovering cancer dependencies in peptide-interacting protein pockets.bioRxiv : the preprint server for biology · 2026Article
- MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations.Journal of chemical information and modeling · 2025Article
- The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives.Journal of molecular biology · 2025Review
- Selective Identification of Allosteric Inhibitors and Co-Drug Combinations Targeting Kinases by Using a Nanopore Tweezer Approach.ACS nano · 2025Article
- Exploring the Allosteric Pathways of Asciminib in the Dual Inhibition of BCR-ABL1.Biomolecules · 2025Article
- Activity of STAMP inhibitors inBlood neoplasia · 2025Article
- Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.Science signaling · 2025Article
- Advances in uncovering the mechanisms of macromolecular conformational entropy.Nature chemical biology · 2025Review
- Nanohydrogel of Curcumin/Berberine Co-Crystals Induces Apoptosis via Dual Covalent/Noncovalent Inhibition of Caspases in Endometrial Cancer Cell Lines: The Synergy Between Pharmacokinetics and Pharmacodynamics.Journal of molecular recognition : JMR · 2025Article
- Review
- Discovery ofMolecules (Basel, Switzerland) · 2025Article
- An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.The Journal of biological chemistry · 2025Article
- Latent allosteric control of protein interactions by ATP-competitive kinase inhibitors.Current opinion in structural biology · 2024Review
- Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation.Biochemistry · 2024Article
- Predicting Mutation-Induced Allosteric Changes in Structures and Conformational Ensembles of the ABL Kinase Using AlphaFold2 Adaptations with Alanine Sequence Scanning.International journal of molecular sciences · 2024Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Selective orthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as "double-drugging", has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not been undertaken. Here, we provide a quantitative framework for double-drugging of kinases employing isothermal titration calorimetry, Förster resonance energy transfer, coupled-enzyme assays, and X-ray crystallography. We discern positive and negative cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with different combinations of orthosteric and allosteric modulators. We find that a conformational equilibrium shift is the main principle governing cooperativity. Notably, for both kinases, we find a synergistic decrease of the required orthosteric and allosteric drug dosages when used in combination to inhibit kinase activities to clinically relevant inhibition levels. X-ray crystal structures of the double-drugged kinase complexes reveal the molecular principles underlying the cooperative nature of double-drugging AurA and Abl with orthosteric and allosteric inhibitors. Finally, we observe a fully closed conformation of Abl when bound to a pair of positively cooperative orthosteric and allosteric modulators, shedding light on the puzzling abnormality of previously solved closed Abl structures. Collectively, our data provide mechanistic and structural insights into rational design and evaluation of double-drugging strategies.
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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.