Abstract Proliferating cell nuclear antigen (PCNA) is a key regulator of at least 11 essential cellular processes, including DNA replication and repair, transcription, cell cycle progression, apoptosis induction, transcription-replication conflict resolution, energy metabolism, chromosome maintenance, mitosis, and immune surveillance. In tumor cells, PCNA exists as a cancer-associated acidic isoform (caPCNA), while non-malignant cells express only a basic isoform (nmPCNA). The absence of caPCNA in normal cells makes it an attractive target for selective cancer therapy. We previously developed AOH1996, a first-in-class small molecule that selectively inhibits caPCNA, inducing apoptosis in cancer cells without detectable toxicity in non-malignant cells. AOH1996 binds to caPCNA, stabilizes its trimeric structure, decreases chromatin association, and suppresses tumor cell proliferation. AOH1996 is orally bioavailable and is currently being evaluated in two first-in-human Phase I clinical trials: one for treatment refractory solid tumors (NCT05227326) and the other for acute myeloid leukemia (NCT06763341). No dose-limiting toxicities have been observed to date, with ongoing dose escalation currently reaching 1110 mg PO BID. In this study, we aimed to enhance the aqueous solubility and pharmacokinetic properties of AOH1996 through strategic single-point heteroatom substitutions. By replacing selected aromatic carbons with nitrogen atoms, we generated a series of quinoline, isoquinoline, and pyridine analogues optimized for liquid oral formulations that will be ultimately compatible with pediatric administration for AML. Structure-activity relationship (SAR) analyses across these three heterocyclic scaffolds identified several analogues with improved solubility, potency, selectivity, and metabolic stability when compared to the clinical lead. For example, introducing two nitrogen atoms into the aromatic regions of one analogue reduced the CLogP to 3.35 (vs. 4.46 for AOH1996) while maintaining IC50 values comparable to the parent compound. This reduction in lipophilicity corresponds to an estimated ∼13-fold increase in aqueous solubility, making this analogue more amenable to liquid formulation for oral administration. Over 30 novel AOH analogues were synthesized and evaluated for antiproliferative activity across eight tumor cell lines (including Molm-13, THP-1, HTB-0225, SK-N-AS, HCT116, U251, and MDA-MB-468), as well as in AML mouse models. Synthetic routes, biological data, and preliminary in vivo results will be presented. Together, these findings lay the groundwork for the next generation of AOH-based therapeutics with improved physicochemical and pharmacological properties suitable for pediatric oncology applications. Citation Format: Pouya Haratipour, Melissa Valerio, Michaela R. Jacobs, Maryam Zangi, Long Gu, Caroline Li, Robert Lingeman, Jennifer Jossart, Jefferson J. Perry, Le Xuan Truong Nguyen, Linda H. Malkas, Robert J. Hickey. Development of hydrophilic and metabolically stable heterocyclic AOH1996 analogues for pediatric AML oral liquid formulations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5140.
Haratipour et al. (Fri,) studied this question.
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