AOH1996 / RLL, City of Hope - LARVOL DELTA

AOH1996, an Inhibitor of PCNA, Sensitises Breast Cancer Cells to Cytotoxic Chemotherapy. (PubMed, Breast Cancer (Dove Med Press)) - "Effects of AOH1996, epirubicin, and/or docetaxel on cell proliferation/survival were assessed using MTT and clonogenic assays. Based on our in vitro data, AOH1996 has potential as a breast cancer therapy and causes chemo-sensitisation in combination with chemotherapies standardly used clinically in primary breast cancer. Future in vivo studies are warranted."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PCNA

AOH1996 Induces Mitotic Catastrophe and DNA Damage to Drive Cytotoxicity in Head and Neck Squamous Cell Carcinoma. (PubMed, J Med Virol) - "In vivo, AOH1996 suppresses tumor growth with minimal toxicity in xenograft models. Together, these findings establish AOH1996 as a promising therapeutic candidate that disrupts mitotic fidelity and induces cancer-selective cytotoxicity in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MYC • PCNA

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: City of Hope Medical Center | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Therapeutic potential of PCNA and HDAC inhibitor combinations in cutaneous T-cell lymphoma and other cancers (AACR 2026) - "Guided by post-translational modification signature enrichment analysis of phosphorylated proteins after AOH1996 treatment, we tested its combination with histone deacetylase inhibitors (HDACi) belinostat and vorinostat...Furthermore, AOH1996 combined with vorinostat or romidepsin, both FDA-approved for treatment of CTCL, showed synergistic growth inhibition in four cell lines derived from CTCL. Mechanistic studies revealed enhanced DNA damage response, cell cycle arrest, and apoptosis in CTCL cells treated with AOH1996 and HDACi. These findings support the therapeutic potential of combining AOH1996 with HDACi for the treatment of cancers, including CTCL."

Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • HDAC3 • PCNA

Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer. (PubMed, Cancer Res Commun) - "We found that subtherapeutic doses of AOH1996 and cisplatin could reduce CaCx xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models."

Journal • Cervical Cancer • Oncology • Solid Tumor • PCNA

Antitumor synergy of AOH1996 and next-generation caPCNA Inhibitors in combination with targeted and chemotherapeutic agents (AACR 2026) - " Both AOH1996 and its next-generation analogs demonstrated synergy with some DNA-damaging and repair inhibiting agents such as cisplatin. AOH1996 and its next-generation analogs exhibit potent synergistic activity with targeted therapies and DNA repair inhibitors, supporting PCNA inhibition as a promising strategy to enhance therapeutic efficacy and overcome resistance. These findings provide a preclinical rationale for clinical development of AOH1996 combination regimens, as well as continued optimization of caPCNA-targeting analogs with superior potency and tolerability."

Combination therapy • Neuroblastoma • Oncology • Solid Tumor • PCNA

Novel PCNA inhibitor AOH1996 synergizes with KRAS-targeted therapies in pancreatic ductal adenocarcinoma (AACR 2026) - "Across KRAS G12C and G12D models, AOH1996 exhibited strong synergy with KRAS inhibitors, including MRTX1133, sotorasib, adagrasib, and RMC-6236. AOH1996 is a promising therapeutic candidate for PDAC, demonstrating potent single-agent activity and strong synergy with clinically relevant KRAS inhibitors across in vitro, ex vivo, and in vivo models. The combination induces profound apoptotic and cell-cycle effects and disrupts key KRAS effector pathways. These results support further translational development of AOH1996-based combination regimens for patients with KRAS-mutant PDAC."

Oncology • Pancreatic Ductal Adenocarcinoma • ANXA5 • KRAS • PCNA

Development of hydrophilic and metabolically stable heterocyclic AOH1996 analogues for pediatric AML oral liquid formulations (AACR 2026) - P1 | "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."

Clinical • First-in-human • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • PCNA

Identification and structural characterization of a novel PCNA-interacting small molecule scaffold (AACR 2026) - "Building on our development of AOH1996, a first-in-class small molecule currently in Phase I clinical evaluation for solid and liquid tumors, we sought to identify additional PCNA-interacting chemotypes that could expand therapeutic opportunities and inform next-generation inhibitor design...Together, these studies establish COH005 as a novel PCNA-interacting scaffold with strong potential for therapeutic development. This work provides a structural and mechanistic foundation for designing next-generation PCNA-targeted agents with improved specificity and pharmacological properties."

Oncology • PCNA

Integrative multiomics and functional studies to identify biomarkers of AOH1996 sensitivity across AML subtypes (AACR 2026) - "Preliminary computational results reveal subtype dependent variation in the relationship between MYC expression and AOH1996 response which aligns with MYC's established role in driving transcriptional load and replication stress and nominating MYC expression as a biologically plausible candidate biomarker. Together, this integrated multiomics and emerging experimental framework supports the feasibility of biomarker-guided evaluation of AOH1996 across AML subtypes and provides a foundation for future translational studies aimed at molecularly informed therapeutic stratification."

Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MYC • PCNA

Kirsten rat sarcoma virus (KRAS) oncoprotein as a new therapeutic target in multiple myeloma (AACR 2026) - "Moreover, combining RMC6236 with anti-myeloma agent venetoclax or a novel anti-PCNA agent AOH1996 significantly reduced cell growth in KRAS mutant and WT MM cells. These findings suggest that the inhibition of MM cell growth by RMC6236 may be linked to the down-regulation of these tumor-associated genes. Ongoing studies aim to further evaluate the anti-myeloma potential of RMC6236."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Sarcoma • Solid Tumor • IL6 • KRAS • PCNA • STAT3

Targeting proliferating cell nuclear antigen via a miRNA-CSC axis as a new therapeutic approach in multiple myeloma (AACR 2026) - "We tested the anti-tumor activity of the novel small molecule PCNA inhibitor AOH-1996 (alone and in combination with either bortezomib or venetoclax) against 5 different sub-types of MM cell lines. These findings clearly suggest that PCNA is a potential therapeutic target in MM. We have demonstrated for the first time that the PCNA inhibitor AOH-1996 shows potent anti-myeloma activity through its effects on several key tumor-associated genes/proteins and miRNAs."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • CDK4 • CDK6 • EZH2 • FGF2 • IL6 • MIR100 • MIR142 • MIR145 • MIR191 • MIR21 • MIR222 • MIR30A • MIR99A • MYC • PCNA • SOX2

AOH1996, a cancer-associated PCNA inhibitor, restores platinum sensitivity in urothelial carcinoma: In vitro and in vivo study (AACR 2026) - "Cisplatin-sensitive (T24, BFTC905) and cisplatin-resistant (T24/R) UC cell lines were treated with AOH1996 alone or in combination with cisplatin or gemcitabine. In a xenograft mouse model of UC, AOH1996 significantly inhibited tumor growth and further potentiated the antitumor effect of cisplatin without causing overt systemic toxicity or significant body weight loss. Together, these findings provide preclinical evidence that targeting caPCNA with AOH1996 exerts robust antitumor activity and restores chemosensitivity in UC, supporting caPCNA inhibition as a promising therapeutic strategy for patients with platinum-resistant disease."

Preclinical • Oncology • Solid Tumor • Urothelial Cancer • ANXA5 • CASP3 • PCNA

The PCNA inhibitor AOH1996 impairs tumor growth and invasiveness in non-small cell lung cancer. (PubMed, Front Pharmacol) - "It also upregulated p53 and its downstream p21 along with activating caspase-3/7 and PARP cleavage. Our findings highlight AOH1996 as a promising therapeutic agent for NSCLC management, with potent effects on cell survival, migration, invasion, and tumour growth."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CDKN1A • PCNA

Advancing AOH1996: Enhanced anticancer activity of next-generation small molecule PCNA inhibitors (AACR 2025) - "Among these, AOH-3M5Me-6F and AOH-3M5Me-6CN emerged as the lead analogues, demonstrating up to nine- and seven-fold improved potency and 38% and 68% higher liver microsome stability, respectively. These findings position these analogues for further development as selective PCNA-targeting cancer therapies."

Oncology • PCNA

Targeting transcription-replication conflict for selective chemotherapy in glioblastoma (AACR 2025) - "The current standard of care for glioblastoma (GBM) is surgical intervention followed by a combination of temozolomide (TMZ) and radiation therapy. GBM cancer cells are, therefore, less likely to develop resistance to AOH1996 through mutagenesis in PCNA. If combined with the existing chemotherapeutic regime and inhibitors of DNA repair pathways, AOH1996 may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability to deliver a durable response in GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PCNA

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: City of Hope Medical Center | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase (AACR 2024) - "Specifically, the histone deacetylase inhibitors belinostat and vorinostat were identified as enriched perturbation signatures. Western blot analysis showed that belinostat decreased protein expression of PCNA, suggestive of mechanistic synergies with AOH1996+belinostat combination therapies. Our proteomic analysis reveals a therapeutic potential of combining AOH1996 and histone deacetylase inhibitors for treating cancer with possibly lower drug dose and toxicities compared to single drug treatment."

Epigenetic controller • Omic analysis • Gastrointestinal Cancer • Neuroblastoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • PCNA

AOH1996: A multi-faceted inhibitor of metastasis via PCNA and tumor microenvironment targeting (AACR 2025) - P1 | "Together, these findings establish AOH1996 as a multi-faceted therapeutic with significant anti-metastatic potential. By targeting both PCNA-dependent processes and the tumor microenvironment, AOH1996 could provide a unique approach for combating metastatic cancers."

Biomarker • Tumor microenvironment • Oncology • Osteosarcoma • Pancreatic Cancer • Sarcoma • Solid Tumor • MYC • PCNA

A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models (AACR 2025) - "We found that KRAS G12D inhibitor (MRTX1133) in combination with AOH1996 enhanced cytotoxicity in several PDAC cell lines at lower MRTX1133 concentrations, potentially reducing toxic side effects. We also observed enhanced efficacy of the chemotherapeutic agent oxaliplatin, which is a platinum compound in the FOLFIRINOX regimen, in combination with AOH1996. Collectively, our results show that AOH1996 is a promising agent for PDAC treatment which potentiates chemotherapy, and targeted KRAS G12D inhibitors. In vivo xenograft studies combining AOH1996 and KRAS inhibitors are ongoing."

Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PCNA

Identification of biomarkers associated with sensitivity to a novel PCNA inhibitor (AOH1996) by CRISPRi screening (AACR 2024) - "We validated the effect of these genes on sensitivity to AOH1996 and identified a panel of target proteins whose up or down-regulation is associated with sensitivity to AOH1996. Some of these proteins are targets of known chemotherapeutic drugs, which may be used in combination with AOH1996 in the clinic."

Biomarker • Oncology • Solid Tumor • PCNA

Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition (AACR 2024) - "The target binding of these analogues was verified by capturing the binary complex of the more polar version of these analogues in the crystal structure. The synthesis, characterization, and detailed biological activities of these promising AOH analogues will be thoroughly described."

Oncology • PCNA

PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma (AACR 2025) - "Inspired by phosphoproteomic analyses of AOH1996-treated cells, we investigated its potential in combination therapy with the histone deacetylase inhibitors (HDACi) vorinostat and belinostat. Enhanced growth inhibition was also observed when AOH1996 was combined with other HDACi, such as domatinostat and panobinostat. These findings highlight the therapeutic potential of AOH1996 in combination with HDACi, particularly for CTCL, and pave the way for further exploration of this approach in cancer treatment."

Epigenetic controller • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • PCNA

Proliferating cell nuclear antigen as a new therapeutic target in multiple myeloma (AACR 2025) - "Increased expression of PCNA has been shown to be associated with an aggressive MM phenotype, making it an attractive therapeutic target. We tested the anti-tumor activity of the novel small molecule PCNA inhibitor AOH-1996 (alone and in combination with either bortezomib or venetoclax) against MM cell lines (MM1.S, SKMM2, RPMI-8226). These findings clearly suggest that PCNA is a potential therapeutic target in MM. We have demonstrated for the first time that the PCNA inhibitor AOH-1996 shows potent anti-myeloma activity through its effects on several key tumor-associated genes and miRNAs. AOH-1996 is currently being evaluated in a Phase I trial."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • CCL3 • CDK4 • CRBN • IL6 • MIR142 • MIR21 • MIR222 • PCNA • VIM

Enhanced lung cancer treatment using AOH1996, a potent PCNA inhibitor (AACR 2024) - "Initially, EGFR TKIs like gefitinib, erlotinib, afatinib and osimertinib deliver remarkable responses, inducing tumor regression and improving overall survival. In this study, we combine AOH1996 and osimertinib as an innovative approach to treating NSCLC cancers with activating EGFR mutations and find that the drug combination: 1.) enhances the killing of NSCLC cell lines with activating EGFR mutations and acquired resistance to TKIs; 2.) enhances the destabilization of PCNA on chromatin; and 3.) causes changes in the localization and colocalization of PCNA and EGFR. We conclude that the combination of AOH1996 and osimertinib holds much potential as an improved treatment regimen for lung cancer patients with activating EGFR mutations."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PCNA