8JNZ

Human ADP-ribosyltransferase 1 (PARP1) catalytic domain bound to a pyrazolopyrimidine carboxamide inhibitor

Summary for 8JNZ

• Entry DOI: 10.2210/pdb8jnz/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, processed C-terminus, 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide, SULFATE ION (3 entities in total)
• Functional Keywords: dna adp-ribosyltransferase 1, parp1, parp inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 79943.21

Authors

Wang, X.Y.,Wang, C.Y.,Zhou, J.,Xu, B.L. (deposition date: 2023-06-06, release date: 2024-06-12, Last modification date: 2025-05-14)

Primary citation

Wang, X.,Wang, C.,Li, J.,Zhou, J.,Xu, B.
Employing a Highly Potent Fluorescence Probe to Discover a PARP-1/2 Binder and the Complex Structures Analysis.
Chemmedchem, :e202500168-e202500168, 2025

PubMed Abstract: Poly (ADP-ribose) polymerases-1/2(PARP-1/2) has been identified as important anti-tumor 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 nM and 1.6 nM towards catPARP-1 and catPARP-2SE. By employing this probe to screen an in-house compound library, compound A bearing a pyrazolo[1,5-a]pyrimidine-3-carboxamide scaffold was disclosed as a structurally novel PARP-1/2 binder, which had dissociation constants of 5.6 μM and 7.9 μM for catPARP-1 and catPARP-2SE in the Isothermal Titration Calorimetry (ITC) assay. Moreover, the crystal structures of compound A in complex with PARP-1 and PARP-2 catalytic domains were solved to reveal the binding modes of this compound, and these two complex structures were analyzed with IGMH method at GFN2-xTB and B3LYP levels. Interestingly, this compound presented significant differences in binding modes within PARP-1 and PARP-2. These results could provide a structural basis for the discovery of novel PARP-1 or PARP-2 selective inhibitors by taking compound A as a template structure.

PubMed: 40204633
DOI: 10.1002/cmdc.202500168

Experimental method

X-RAY DIFFRACTION (2.84 Å)