Poly-publications on the polypharmacology of kinase/bromodomains dual inhibitors

When you consider how vast the chemical space is and how restricted the topology and chemical environment of a specific pocket in a protein is, it’s quite surprising we can find molecules that the protein was not evolved to bind that can nonetheless bind and inhibit it potently. It is therefore even more surprising when a single molecule can potently hit two completely unrelated (by sequence, by structure and by function) proteins. Thus, when two independent groups publish such dual kinase/bromodomain inhibitors a week a part from each other, the mind reels.

Kinases are very prevalent and important drug targets, and as such the arsenal of potent tool compounds and clinical candidates of kinase inhibitors is huge. Bromodomains are domains that mediate protein-protein interactions through the binding of acetylated-lysine containing peptides, and are heavily involved in epigenetics. In recent years they received a lot of attention, and are one of the poster children of protein-protein interaction inhibitors targets.

These Bromodomains have nothing to do with kinases. They don’t look like one. They don’t bind ATP. But it would still be helpful to find a molecule that would inhibit both – bromodomain containing proteins are often involved in oncogenic pathways, and such a dual inhibitor could be more efficacious in cancers driven by that pathway and more tolerant to resistance mutations.

To find such molecules, in what seems like an astounding coincidence, two independent efforts were lunched and recently published a week apart in ACS Chemical Biology and Nature Chemical Biology. The good news are that both groups succeeded in finding such dual-inhibitors. More over they found the SAME dual-inhibitors. This is amazing reproducibility!

Both groups used a kinase inhibitor library of ~600 compounds to screen for binding against BRD4. The first group (Ember et. al.) used co-crystallization screening and discovered 14 kinase inhibitors that are able to bind BRD4. The second group (Ciceri et. al.) used an AlphaScreen and discovered 9 inhibitors (Eloquently summarized for easy digestion here). Reassuringly the most potent compounds in both screens were a PLK inhibitor BI-2536 (BRD4 IC50 reported by both 25nM / 37nM) and a JAK inhibitor TG101209  (BRD4 IC50= 130nM / 123nM). Both groups showed the selectivity of these compounds across different bromodomains, and both groups solved the structures of the compounds in complex with BRD4 (E.g. BI-2536 PDB: 4OGI (Ciceri)  PDB: 4O74 (Ember)) The compound binding mode superposes perfectly between the two independent structures.

Ember et. al. solved the structures of 15 such complexes and show that the kinase hinge binding motifs of the different inhibitors can adopt several binding modes in the bromodomain binding pocket, and thus suggest that this class of domains are potential off-targets to many kinase inhibitors. Ciceri et. al. exemplify the advantages of such dual-inhibitors using AML cells – an oncology indication that is often driven by BET and mutant FLT3, as well as 12 other primary human cell disease models.

Altogether these two works strongly reinforce each other and make a very compelling case for the design of polypharmacology.


Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, & Schönbrunn E (2014). Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors. ACS chemical biology PMID: 24568369
Ciceri P, Müller S, O’Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, & Knapp S (2014). Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nature chemical biology, 10 (4), 305-312 PMID: 24584101

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  • sofenza

    These Bromodomains have nothing to do with kinases. They don’t look like one. They don’t combine ATP. But it would still be necessary to discover a compound that would restrict both – bromodomain containing necessary protein are often engaged in oncogenic routes, and such a double chemical could be more effective in malignancies motivated by that process and more resistant to level of resistance strains.

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