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Dual kinase-bromodomain inhibitors for rationally designed polypharmacology

Pietro Ciceri1, Susanne Müller2, Alison O'Mahony3

  • 11] KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA. [2].

Nature Chemical Biology
|March 4, 2014
PubMed

Insights

Several clinical kinase inhibitors also inhibit bromodomains, acting as dual kinase-bromodomain inhibitors. This discovery offers a new strategy for single-agent polypharmacological targeting in cancer therapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Structural Biology

Background:

  • Targeted cancer therapies often involve inhibiting multiple kinases to improve response durability.
  • Developing single agents with multitarget profiles is challenging, leading to complex combination therapies.
  • Bromodomain proteins, epigenetic readers, are emerging as promising cancer therapeutic targets.

Purpose of the Study:

  • To identify existing clinical kinase inhibitors that also possess bromodomain inhibitory activity.
  • To explore the potential of these dual-acting agents for single-agent polypharmacological cancer targeting.
  • To elucidate structure-activity relationships for designing novel dual kinase-bromodomain inhibitors.

Main Methods:

  • Screening of clinical kinase inhibitors for activity against bromodomain targets, specifically BRD4.
  • Co-crystallography to determine the binding modes of inhibitors.
  • Structure-activity relationship (SAR) analysis.

Main Results:

  • Several clinical kinase inhibitors demonstrated nanomolar potency against bromodomains.
  • BI-2536 (PLK1 inhibitor) and TG-101348 (JAK2-FLT3 inhibitor) were identified as potent BRD4 inhibitors.
  • Co-crystal structures revealed key interactions enabling dual inhibition.

Conclusions:

  • Clinical kinase inhibitors can possess dual kinase-bromodomain inhibitory activity, representing a new class of therapeutic agents.
  • This dual activity offers a rational approach for single-agent polypharmacology, targeting independent oncogenic pathways.
  • The identified design features provide a platform for developing novel, effective dual kinase-bromodomain inhibitors.

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