1. Biochemistry and Chemical Biology
  2. Computational and Systems Biology

Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting

  1. Ian R Outhwaite
  2. Sukrit Singh
  3. Benedict-Tilman Berger
  4. Stefan Knapp
  5. John D Chodera
  6. Markus A Seeliger  Is a corresponding author
  1. Stony Brook University, United States
  2. Memorial Sloan Kettering Cancer Center, United States
  3. Goethe University Frankfurt, Germany
https://doi.org/10.7554/eLife.86189
Share this article
Cite this article
  1. Ian R Outhwaite
  2. Sukrit Singh
  3. Benedict-Tilman Berger
  4. Stefan Knapp
  5. John D Chodera
  6. Markus A Seeliger
(2023)
Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting
eLife 12:e86189.
https://doi.org/10.7554/eLife.86189
  2. Download BibTeX
  3. Download .RIS

Abstract

Kinase inhibitors are successful therapeutics in the treatment of cancers and autoimmune diseases and are useful tools in biomedical research. However, the high sequence and structural conservation of the catalytic kinase domain complicates the development of selective kinase inhibitors. Inhibition of off-target kinases makes it difficult to study the mechanism of inhibitors in biological systems. Current efforts focus on the development of inhibitors with improved selectivity. Here, we present an alternative solution to this problem by combining inhibitors with divergent off-target effects. We develop a multicompound-multitarget scoring (MMS) method that combines inhibitors to maximize target inhibition and to minimize off-target inhibition. Additionally, this framework enables optimization of inhibitor combinations for multiple on-targets. Using MMS with published kinase inhibitor datasets we determine potent inhibitor combinations for target kinases with better selectivity than the most selective single inhibitor and validate the predicted effect and selectivity of inhibitor combinations using in vitro and in cellulo techniques. MMS greatly enhances selectivity in rational multitargeting applications. The MMS framework is generalizable to other non-kinase biological targets where compound selectivity is a challenge and diverse compound libraries are available.

Data availability

Instructions to run MMS, code, datasets, and MMS results are available at: https://github.com/iouthwaite/inhibitor_combinations

Article and author information

Author details

  1. Ian R Outhwaite

    Department of Pharmacological Sciences, Stony Brook University, Stony Brook, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2037-3261

  2. Sukrit Singh

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1914-4955

  3. Benedict-Tilman Berger

    Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
    Competing interests
    Benedict-Tilman Berger, is the CEO and a shareholder of CELLinib GmbH, Frankfurt, Germany..

  4. Stefan Knapp

    Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5995-6494

  5. John D Chodera

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    John D Chodera, is a current member of the Scientific Advisory Boards of OpenEye Scientific Software, Interline Therapeutics, and Redesign Science. The Chodera laboratory receives or has received funding from the National Institute of Health, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, XtalPi, Interline Therapeutics, and the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0542-119X

  6. Markus A Seeliger

    Department of Pharmacological Sciences, Stony Brook University, Stony Brook, United States
    For correspondence
    markus.seeliger@stonybrook.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0990-1756

Funding

National Institutes of Health (R35GM119437)

  • Markus A Seeliger

National Institutes of Health (T32GM136572)

  • Ian R Outhwaite

National Institutes of Health (R01GM121505)

  • John D Chodera

Damon Runyon Cancer Research Foundation (DRQ-14-22)

  • Sukrit Singh

National Institutes of Health (T32GM008444)

  • Ian R Outhwaite

Structural Genomics Consortium

  • Stefan Knapp

German Translational Cancer Network

  • Stefan Knapp

Deutsche Forschungsgemeinschaft (1399)

  • Benedict-Tilman Berger
  • Stefan Knapp

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Outhwaite et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,850
    views
  • 265
    downloads
  • 1
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ian R Outhwaite
  2. Sukrit Singh
  3. Benedict-Tilman Berger
  4. Stefan Knapp
  5. John D Chodera
  6. Markus A Seeliger
(2023)
Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting
eLife 12:e86189.
https://doi.org/10.7554/eLife.86189

Share this article

https://doi.org/10.7554/eLife.86189

Categories and tags

Further reading

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    On the role of VP3-PI3P interaction in birnavirus endosomal membrane targeting

    Flavia A Zanetti, Ignacio Fernandez ... Laura Ruth Delgui
    Research Article

    Birnaviruses are a group of double-stranded RNA (dsRNA) viruses infecting birds, fish, and insects. Early endosomes (EE) constitute the platform for viral replication. Here, we study the mechanism of birnaviral targeting of EE membranes. Using the Infectious Bursal Disease Virus (IBDV) as a model, we validate that the viral protein 3 (VP3) binds to phosphatidylinositol-3-phosphate (PI3P) present in EE membranes. We identify the domain of VP3 involved in PI3P-binding, named P2 and localized in the core of VP3, and establish the critical role of the arginine at position 200 (R200), conserved among all known birnaviruses. Mutating R200 abolishes viral replication. Moreover, we propose a two-stage modular mechanism for VP3 association with EE. Firstly, the carboxy-terminal region of VP3 adsorbs on the membrane, and then the VP3 core reinforces the membrane engagement by specifically binding PI3P through its P2 domain, additionally promoting PI3P accumulation.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    Cellular Energy Production: Mycofactocin and the mycobacterial electron transport chain

    Stephanie M Stuteley, Ghader Bashiri
    Insight

    In the bacterium M. smegmatis, an enzyme called MftG allows the cofactor mycofactocin to transfer electrons released during ethanol metabolism to the electron transport chain.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics

    Electrostatics of salt-dependent reentrant phase behaviors highlights diverse roles of ATP in biomolecular condensates

    Yi-Hsuan Lin, Tae Hun Kim ... Hue Sun Chan
    Research Article

    Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, for example, reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.