2026-10-12T23:35:08Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33935645 2026-09-18T13:11:49Z category_1 category_4 category_12 category_13 category_14 category_19 category_21 category_873 category_46 category_61 category_64 category_132 category_133 portal_63 item_type_3 month_year_09_2026

Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA Pouya Haratipour (5420441) Maryam Zangi (10306878) Long Gu (371782) Caroline M. Li (3609314) Mahshid Yaghoubi (12884822) Jennifer Jossart (6752156) Robert G. Lingeman (3609311) Katerina L. Aris (25072217) Sebastian O. Wendel (744817) Fan Meng (60551) Frank Xia (25072220) Asfar S. Azmi (9251985) Timothy W. Synold (2714050) Mustafa Raoof (377982) Nicholas A. Wallace (25072223) J. Jefferson P. Perry (7473470) Linda H. Malkas (15011148) Robert J. Hickey (550809) Biophysics Biochemistry Cell Biology Genetics Molecular Biology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Developmental Biology Cancer Infectious Diseases Plant Biology tumor cells express pancreatic cancer cells nonmalignant cells express generation aoh analogues enhanced pharmacological properties anticancer therapeutic agents selectively inhibits capcna previously identified aoh1996 generation aoh1996 analogues 60 </ b 58 </ b capcna ), parent molecule naphthoyl moiety methyl substitutions mediated activities lower concentrations incorporating 3 exhibited 9 critical role basic isoform based assays acidic isoform Proliferating Cell Nuclear Antigen (PCNA) plays a critical role in at least 11 distinct cellular pathways. Tumor cells express an acidic isoform of the protein (caPCNA), while nonmalignant cells express only a basic isoform (nmPCNA). We previously identified AOH1996 as a first-in-class, orally bioavailable small molecule that selectively inhibits caPCNA-mediated activities. In this study, second-generation AOH analogues with enhanced pharmacological properties were created through scaffold optimization, with AOH2.60 and AOH2.58 incorporating 3-methoxy-5-methyl substitutions (Scaffold A) and, respectively, 6-fluoro or 6-cyano on the 1-naphthoyl moiety (Scaffold D). The compounds AOH2.60 and AOH2.58 exhibited 9.6-fold and 6.6-fold increased potency across multiple cancer cell lines without affecting normal cells, and 38% and 68% greater microsomal stability relative to AOH1996, warranting further development as anticancer therapeutic agents. In cell-based assays, both compounds induced robust G2/M arrest at lower concentrations than the parent molecule and significantly enhanced transcription–replication conflicts in pancreatic cancer cells. 2026-09-18T00:00:00Z Dataset Dataset 10.1021/acs.jmedchem.6c01185.s003 https://figshare.com/articles/dataset/Second-Generation_AOH1996_Analogues_with_Enhanced_Pharmacological_Properties_for_Targeting_PCNA/33935645 CC BY-NC 4.0