Identification of “Preferred” Human Kinase Inhibitors for Sleeping Sickness Lead Discovery. Are Some Kinases Better than Others for Inhibitor Repurposing?

Abstract

A kinase-targeting cell-based high-throughput screen (HTS) against Trypanosoma brucei was recently reported, and this screening set included the Published Kinase Inhibitor Set (PKIS). From the PKIS was identified 53 compounds with pEC50 ≥ 6. Utilizing the published data available for the PKIS, a statistical analysis of these active antiparasitic compounds was performed, allowing identification of a set of human kinases having inhibitors that show a high likelihood for blocking T. brucei cellular proliferation in vitro. This observation was confirmed by testing other established inhibitors of these human kinases and by mining past screening campaigns at GlaxoSmithKline. Overall, although the parasite targets of action are not known, inhibitors of this set of human kinases displayed an enhanced hit rate relative to a random kinase-targeting HTS campaign, suggesting that repurposing efforts should focus primarily on inhibitors of these specific human kinases. We therefore term this statistical analysis-driven approach “preferred lead repurposing”.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Having originally been designed as a multi‐kinase inhibitor, compound 23 has been shown to potently inhibit several members of the human cyclin‐dependent kinase family in addition to human tyrosine kinase EPHA2 . Accordingly, compound 23 was selected as part of a subset of preferred human kinase inhibitors for a target‐repurposing programme to uncover new antitrypanosomal agents . While the specific MOA was not confirmed in this study, 23 displayed potent antitrypanosomal activity.…”

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

“…The same authors reported that alvocidib inhibited the growth of L. mexicana mexicana (MNYC/BZ/62/M379) promastigotes in a dose‐dependent manner in vitro. At 1.0 μ m concentration, alvocidib caused a complete arrest of promastigote growth, while a lower concentration resulted in partial growth inhibition . Alvocidib also inhibited the recombinant CRK3his/CYCAhis with an IC 50 of 0.102 μ m , a similar value as compared with IC 50 of 0.1 μ m for Lmx CRK3his .…”

“…Compounds grouped by similarity of the main human kinase targets are reported in Figures –. Some of them have been indicated as potential T. brucei growth inhibitors according to a statistical analysis driven approach performed on a high throughput screening released by GlaxoSmithKline . In this study, among over 224 human kinases, 29 kinases, defined as Preferred Human Kinases, were statistically selected, and inhibitors of these kinases are indicated to have a better likelihood of activity in the parasite.…”

“…Moderate activity has been shown against L. major promastigote form with EC 50 of 0.39 μ m for both compounds . Evaluated on Tb ERK8, milciclib and AZD5438 have inhibited the kinase activity up to 20 % or less, but no selectivity over mammalian cells has been observed …”

“…Other repurposed human CDK inhibitors include SNS032, JNJ7706621, BMS265246 and AT7519 (Figure ) . These inhibitors have proven good activity against T. brucei parasites (Lister 427 strain) with EC 50 ranging between 0.13–0.50 μ m , but little to no effect on L. major and T. cruzi intracellular amastigote (Tulahuén strain) with the only exception of BMS265246, which has a reported moderate L. major promastigote growth inhibition with EC 50 of 0.25 μ m .…”