molecules of the month

compound 1

selective inhibitor of unphosphorylated HPK1

non-ATP competitive, IC50 = 1.2 µM

from 700k cmpd HTS for non-ATP comp. inh.


Janssen R&D, Spring House, PA

Chemical structure of compound 1 Janssen non-ATP competitive HPK1 inhibitor
1 min read

The Janssen non-ATP competitive HPK1 inhibitor, “compound 1,” was identified from a screening cascade specifically looking for allosteric inhibitors, which may provide a selectivity advantage over ATP-competitive starting points. Reviewer Adi Murthy says, “Specificity may prove challenging for HPK active site inhibitors since it belongs to a large family of Ste20 genes that act as MAP4Ks, all with high kinase domain homology.” Reviewer and nominator Callie Bryan says, “The publication summarizes work towards allosteric inhibitors of HPK1 targeting the inactive conformation through application of a cascade assay designed to target full-length, inactive HPK1. In doing so, molecules that attenuate autophosphorylation and potentially interfere with active HPK1 dimer formation were discovered without strong competition with ATP. This strategy could prove fruitful to other kinases where allosteric…

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