LAUSR

Poly (ADP‐ribose) polymerases‐1/2 (PARP‐1/2) has been identified as important antitumor drug targets and the development of PARP‐1/2 inhibitors featuring novel structures is still a promising strategy for cancer treatments. In this work, a highly potent PARP‐1/2 probe with a quinazolinone scaffold was designed and synthesized, showing dissociation constants (Kd) of 2.07 and 1.6 nM toward catPARP‐1 and catPARP‐2SE, respectively. By employing this probe to screen an in‐house compound library, compound A bearing a pyrazolo[1,5‐a]pyrimidine‐3‐carboxamide scaffold is disclosed as a structurally novel PARP‐1/2 binder, which has dissociation constants of 5.6 and 7.9 μM for catPARP‐1 and catPARP‐2SE, respectively, in the isothermal titration calorimetry (ITC) assay. Moreover, the crystal structures of compound A in complex with PARP‐1 and PARP‐2 catalytic domains are solved to reveal the binding modes of this compound and these two complex structures are analyzed with IGMH method at GFN2‐xTB and B3LYP levels. Interestingly, this compound presents significant differences in binding modes within PARP‐1 and PARP‐2. These results can provide a structural basis for the discovery of novel PARP‐1 or PARP‐2 selective inhibitors by taking compound A as a template structure.