3L3M

PARP complexed with A927929

Summary for 3L3M

• Entry DOI: 10.2210/pdb3l3m/pdb
• Related: 2RCW 2RD6 3GJW 3GN7
• Descriptor: Poly [ADP-ribose] polymerase 1, 2-{2-fluoro-4-[(2S)-piperidin-2-yl]phenyl}-1H-benzimidazole-7-carboxamide (3 entities in total)
• Functional Keywords: protein-inhibitor complex, acetylation, adp-ribosylation, dna damage, dna repair, dna-binding, glycosyltransferase, metal-binding, nad, nucleus, phosphoprotein, transcription, transcription regulation, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P09874
• Total number of polymer chains: 1
• Total formula weight: 39507.19

Authors

Park, C.H. (deposition date: 2009-12-17, release date: 2010-06-23, Last modification date: 2024-04-03)

Primary citation

Penning, T.D.,Zhu, G.D.,Gong, J.,Thomas, S.,Gandhi, V.B.,Liu, X.,Shi, Y.,Klinghofer, V.,Johnson, E.F.,Park, C.H.,Fry, E.H.,Donawho, C.K.,Frost, D.J.,Buchanan, F.G.,Bukofzer, G.T.,Rodriguez, L.E.,Bontcheva-Diaz, V.,Bouska, J.J.,Osterling, D.J.,Olson, A.M.,Marsh, K.C.,Luo, Y.,Giranda, V.L.
Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor.
J.Med.Chem., 53:3142-3153, 2010

PubMed Abstract: We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

PubMed: 20337371
DOI: 10.1021/jm901775y

Experimental method

X-RAY DIFFRACTION (2.5 Å)