Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in ATAD2 inhibition and selectivity over BRD4.

Id e n tific a tio n of a N ov el O r ally Bio av ail a bl e ERK 5 In hi bit o r wi t h S el e c tivity ov e r p 3 8 a n d α BRD 4. E u r o p e a n Jou r n al of M e di ci n al C h e mi s t ry, 1 7 8 . p p. 5 3 0-5 4 3. IS S N 0 2 2 3-5 2 3 4 Do w nlo a d e d fro m: h t t

Myers, S. M. et al. (2016) High-throughput screening and hit validation of extracellular-related kinase 5 (ERK5) inhibitors. ACS Combinatorial Science, 18(8), pp. 444-455. (doi:10.1021/acscombsci.5b00155) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it. AbstractThe extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP Progressive Binding System, and used to identify hits from a library of 57,617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and re-assay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits.Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.