•  Kyle E. Denton, Will E. Evenson, Kelly A. McCarthy, Douglas Marcotte, Brian Raimundo, Marie Katz, Fangrui Wu, Kingsley Appiah, Mark Rekhter, Rachael R. Jetson, Eric Stangeland | Discovery Sciences, Valo Health, 75 Hayden Ave, Lexington, Massachusetts

Poster: Selectivity Assessment through Parallel Selections: A Case Study with Phosphodiesterases


Phos­pho­di­esteras­es (PDEs) are a super­fam­i­ly of enzymes which cat­alyze the hydrol­y­sis of cAMP and/​or cGMP and are tar­gets of inter­est for car­dio­vas­cu­lar dis­eases. We sought to iden­ti­fy sub­type-spe­cif­ic inhibitors using Valo’s DEL plat­form. The DEL sec­tions inter­ro­gat­ed sev­er­al tar­get forms of each sub­type and includ­ed com­pe­ti­tion selec­tions with a known PDE-binder to enable pro­fil­ing of active site binders. Through the infor­mat­ic analy­sis of the selec­tion data, we depri­or­i­tized struc­tur­al clus­ters that showed pan-sub­type enrich­ment and only focused on sub­type-spe­cif­ic clus­ters. These efforts yield­ed numer­ous struc­tural­ly dis­tinct series with >1,000-fold inhi­bi­tion selec­tiv­i­ty for near­ly all com­pounds and with a hit rate of 75% (IC50 < 1 μM).