8GLA

Co-crystal structure of caPCNA bound to the AOH1996 derivative, AOH1996-1LE

Summary for 8GLA

• Entry DOI: 10.2210/pdb8gla/pdb
• Descriptor: Proliferating cell nuclear antigen, N-[2-(3-methoxyphenoxy)phenyl]-N~2~-(naphthalene-1-carbonyl)-L-alpha-glutamine, CHLORIDE ION (3 entities in total)
• Functional Keywords: pcna, transcription-replication conflict, dna replication stress, dna repair, aoh1160, aoh1996, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 118457.79

Authors

Jossart, J.,Perry, J.J. (deposition date: 2023-03-21, release date: 2023-07-26, Last modification date: 2024-10-16)

Primary citation

Gu, L.,Li, M.,Li, C.M.,Haratipour, P.,Lingeman, R.,Jossart, J.,Gutova, M.,Flores, L.,Hyde, C.,Kenjic, N.,Li, H.,Chung, V.,Li, H.,Lomenick, B.,Von Hoff, D.D.,Synold, T.W.,Aboody, K.S.,Liu, Y.,Horne, D.,Hickey, R.J.,Perry, J.J.P.,Malkas, L.H.
Small molecule targeting of transcription-replication conflict for selective chemotherapy.
Cell Chem Biol, 30:1235-, 2023

PubMed Abstract: Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.

PubMed: 37531956
DOI: 10.1016/j.chembiol.2023.07.001

Experimental method

X-RAY DIFFRACTION (3.77 Å)