AOH1996 / RLL, City of Hope - LARVOL DELTA

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

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

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

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

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

Synthesis and Anticancer Evaluation of PCNA Inhibitor AOH1996 Analogs in Cancer Cell Cultures. (PubMed, Molecules) - "Several active compounds were predicted to inhibit P-glycoprotein, suggesting their potential to overcome multidrug resistance. Overall, compounds 2b and 3b showed relatively favorable predicted profiles and can serve as useful lead scaffolds for further optimization and experimental validation."

Journal • Preclinical • Brain Cancer • Breast Cancer • Cardiovascular • Glioblastoma • Oncology • Solid Tumor • PCNA

Screening for novel chemical scaffolds targeting PCNA identifies the Hsp90alpha inhibitor SNX-2112. (PubMed, Curr Res Struct Biol) - "However, we recently developed a PCNA inhibitor, AOH1996, which acts as a molecular glue between PCNA and RNA Pol II promoting selective killing of cancer cells through the induction of transcription-replication conflicts. We coupled artificial intelligence-based computational screens with thermal shift assays in a search for novel hit compounds, and characterized a key hit through protein crystallography, a cellular thermal shift assay and protein frustration calculations. Notably, we discovered that the Hsp90α inhibitor, SNX-2112, binds to PCNA within the major PIP-box binding pocket, revealing a new chemical scaffold for the potential development of novel PCNA-targeting inhibitors."

Journal • Infectious Disease • Oncology • Targeted Protein Degradation • CDC37 • HSP90AA1 • PCNA

Targeting the master of the replication fork-PCNA. (PubMed, Pathol Res Pract) - "Several agents-most notably the APIM peptide ATX-101 and the allosteric small molecule AOH1996-have progressed beyond preclinical testing and are being evaluated as monotherapies or in combination with radiotherapy and genotoxic chemotherapies in early clinical studies. This review synthesizes the mechanistic rationale, therapeutic modalities, and development landscape of PCNA-targeted interventions, highlighting their potential to improve anticancer efficacy while mitigating toxicity."

Journal • Review • Oncology • PCNA

PCNA Inhibition Enhances the Antitumor Activity of KRAS-Targeted Therapies in Pancreatic Cancer. (PubMed, bioRxiv) - "Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo , the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation."

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

Disrupting Mitochondrial Dynamics and Metabolism in Leukemic Stem Cells through Mitochondrial PCNA Inhibition: The Role of AOH1996 (ASH 2024) - "The BCL-2 inhibitor venetoclax (VEN) has been shown to impact on the oxidative metabolism that supports LSC homeostasis. We demonstrated a better activity when AOH1996 is combined with VEN. While VEN is FDA-approved for AML, AOH1996 is in clinical trials for solid tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • CD34 • CD38 • FLT3 • PCNA • PTPRC

Assessment of Methods in AOH1996 Studies for Pancreatic Ductal Adenocarcinoma Therapy. (PubMed, Gastroenterology) - No abstract available

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

The PCNA inhibitor AOH1996 suppresses cancer stemness and enhances anti-PD1 immunotherapy in squamous cell carcinoma. (PubMed, Stem Cell Res Ther) - "Taken together, our results demonstrated that AOH1996 suppressed tumor growth, eliminated cancer stem cells (CSCs), and synergistically enhanced the efficacy of anti-PD1 immunotherapy in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • PCNA • TBK1

AOH1996 for the Treatment of Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=92 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Jan 2026 ➔ Sep 2029 | Trial primary completion date: Jan 2026 ➔ Sep 2029

First-in-human • Trial completion date • Trial primary completion date • Leiomyosarcoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Ovarian Cancer • Pancreatic Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Synovial Sarcoma

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 | Trial completion date: Aug 2027 ➔ Jan 2027 | Trial primary completion date: Aug 2027 ➔ Jan 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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 | Not yet recruiting ➔ Recruiting

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

A Phase 1 Study of AOH1996 in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: City of Hope Medical Center | N=30 ➔ 12 | Trial completion date: Jan 2027 ➔ Aug 2027 | Trial primary completion date: Jan 2027 ➔ Aug 2027

Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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

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

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

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