Evolution of kinase polypharmacology across HSP90 drug discovery

Abstract

Highlights d Characterization of kinase polypharmacology landscape for HSP90 inhibitors d Ganetespib and luminespib display unique polypharmacology d Kinase polypharmacology evolved during optimization to discover luminespib d Earlier characterization of polypharmacology in drug discovery is recommended

Developing Isoxazole as a Native Photo‐Cross‐Linker for Photoaffinity Labeling and Chemoproteomics

“…It is noted that Antolin et al. recently revealed several kinases as potential off‐targets of Luminespib, [25] demonstrating the significance of unique kinase polypharmacology in developing Hsp90 inhibitors . On the other hand, kinases were not prominently enriched in our chemoproteomic experiments.…”

“…[23] Interestingly, PTGES2, an isomerase involved in prostaglandin E2 metabolism, was recently developed as a promising therapeutic target for COVID-19 treatment. [24] It is noted that Antolin et al recently revealed several kinases as potential off-targets of Luminespib, [25] demonstrating the significance of unique kinase polypharmacology in developing Hsp90 inhibitors . On the other hand, kinases were not prominently enriched in our chemoproteomic experiments.…”

EFMC: Trends in Medicinal Chemistry and Chemical Biology

“…A recent study evaluated the kinase inhibition of these heat shock protein HSP90 inhibitors. [149] Experimental screening of their inhibitory potency against a kinase panel revealed distinct coverage of the orthosteric ATPsite binders, with ganetespib and luminespib respectively inhibiting 21 and 2 out of 382 kinases, and a retrospective analysis showed that the kinase polypharmacology of luminespib markedly evolved during the hit-to-lead drug discovery process. Combinations of HSP90 and kinase inhibitors are potential cancer treatment, and kinases lend themselves to ABPP due to the availability of potent, cell-permeable probes, which could facilitate repurposing strategies.…”

“…Ganetespib and luminespib are drug candidates for the treatment of cancer. A recent study evaluated the kinase inhibition of these heat shock protein HSP90 inhibitors [149] . Experimental screening of their inhibitory potency against a kinase panel revealed distinct coverage of the orthosteric ATP‐site binders, with ganetespib and luminespib respectively inhibiting 21 and 2 out of 382 kinases, and a retrospective analysis showed that the kinase polypharmacology of luminespib markedly evolved during the hit‐to‐lead drug discovery process.…”

Data-Driven Global Assessment of Protein Kinase Inhibitors with Emphasis on Covalent Compounds

“…Inhibition of the catalytic phosphate transfer activity, which is essential for many signal transduction events, is by far the most widely applied strategy for therapeutic intervention of abnormal kinase functions. , Protein kinase inhibitors (PKIs) are used in a variety of therapeutic areas. The first PKIs marketed as drugs were developed for cancer treatment, and their therapeutic effects largely depended on multi-kinase engagement and the resulting polypharmacology. ,,, In other therapeutics areas such as inflammatory or metabolic diseases, kinase-selective inhibitors are preferentially used, especially for the treatment of chronic medical conditions. ,,, PKIs are distinguished by different mechanisms of actions. , Most kinase inhibitors bind to the adenosine triphosphate (ATP) cofactor binding site or proximal to this site (type I, I1/2, and II inhibitors) and compete with ATP binding. Since the ATP binding site is mostly conserved across the human kinome, these inhibitors are expected to have multi-kinase activity.…”