8he7 | pdb_00008he7
ADP-ribosyltransferase 1 (PARP1) catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
Structural highlights
FunctionPARP1_HUMAN Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.[1] [2] [3] [4] Publication Abstract from PubMedPARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC(50) = 0.94 nM) and PARP-2 (IC(50) = 0.87 nM) but also toward PARP-7 (IC(50) = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors. Discovery of Quinazoline-2,4(1H,3H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors horizontal line Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.,Zhou J, Du T, Wang X, Yao H, Deng J, Li Y, Chen X, Sheng L, Ji M, Xu B J Med Chem. 2023 Oct 26;66(20):14095-14115. doi: 10.1021/acs.jmedchem.3c01152. , Epub 2023 Oct 16. PMID:37843892[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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