TT001 / Ting Therap - LARVOL DELTA

Cell cycle dependent and independent regulation of AKT activity in germinal center B-cell-like diffuse large B-cell lymphoma – a dual role of cyclin dependent kinase 2 (ASH 2025) - "In contrast, palbociclib (CDK4/6 inhibitor) did not haveany significant AKT inhibitory effect...The PTEN inhibitor HOpic (PTENi) is able to increase AKT activitywithin minutes, but the PTENi-induced increase of AKT activity was completely eliminated by CDK2inhibition (AZD-5438 - CDK1/2/9 inhibitor)...Additionally,CDK2 seems to be involved in a critical feed-forward AKT activation loop. PTEN deletion leads to easierG1-S transition on the Background of increased AKT and metabolic activity.Supported by MHCR (DRO - VFN00064165), National Institute for Cancer Research (EXCELES -LX22NPO5102), and MEYSCR (Cooperatio, SVV 260637)."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • CCNA2 • CDK1 • CDK2

Effective therapeutic targeting of CTNNB1-mutant hepatoblastoma with WNTinib. (PubMed, Mol Oncol) - "WNTinib's efficacy was assessed in three animal models (n = 48): (a) patient-derived xenograft (PDX) HB tumors (n = 5 CTNNB1-mutant, n = 1 CTNNB1 wild-type) implanted in NSG mice; (b) PDX-derived TT001- and (c) HepG2-HB cells subcutaneously implanted in Fox1nu mice; and in two patient-derived organoids from CTNNB1-mutant HBs. In HB organoids, WNTinib demonstrated greater efficacy than standard-of-care cisplatin (P = 0.009, org-1), and its antitumor effect was further enhanced when combined with chemotherapy (P = 0.01, org-1; P = 0.007, org-22). WNTinib delays tumor progression and increases survival in CTNNB1-mutated HB models, providing rationale to explore its use in human HB."

Journal • Hepatoblastoma • Liver Cancer • Oncology • Pediatrics • Solid Tumor • CTNNB1

Effect of novel metabotropic glutamate receptor 5 antagonist on gastroesophageal reflux in dogs during anaesthesia. (PubMed, J Small Anim Pract) - "Administration of metabotropic glutamate receptor 5 antagonist TT001 as a single intravenous bolus injection before or after pre-anaesthetic drugs has limited effect on the incidence of gastroesophageal reflux in anaesthetised dogs."

Journal • Anesthesia • Gastroenterology • Gastroesophageal Reflux Disease • Infectious Disease • Pneumonia • Respiratory Diseases

Dual CDK and MEK Inhibition potentiates CD8+ T cell-mediated antitumor immunity by inducing pyroptotic cell death in high-mutational head and neck cancer. (PubMed, J Exp Clin Cancer Res) - "Our findings indicate that the combination of AZD5438 and PD0325901 holds therapeutic potential for the treatment of HPV (-) HNSCC, particularly in tumors with a high mutational burden. By targeting complementary pathways, this combination may improve treatment outcomes in this aggressive cancer subtype."

Journal • Tumor mutational burden • Head and Neck Cancer • Inflammatory Arthritis • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • CD8 • GSDME • TMB

Oral AZD5438 is a clinically translatable otoprotectant against cisplatin-induced hearing loss. (PubMed, Neoplasia) - "does not reduce cisplatin's anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy."

Journal • Genito-urinary Cancer • Oncology • Otorhinolaryngology • Solid Tumor • Testicular Cancer

Design, synthesis, and activity evaluation of selective CDK9 inhibitors containing indazole fragments. (PubMed, Bioorg Chem) - "This study designed and synthesized two series (A and B) of 28 unreported compounds based on rational structural modification of the lead compound AZD5438...Mechanistic studies demonstrated that B11 induces apoptosis in HCT116 cells by elevating intracellular ROS levels through suppression of anti-apoptotic protein expression and activating the caspase-3 pathway. In conclusion, compound B11 may serve as a novel selective CDK9 inhibitor worthy of further development for colorectal cancer treatment."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CASP3

N-(Pyridin-3-yl)pyrimidin-4-amine analogues as potent CDK2 inhibitors: an in silico investigative approach. (PubMed, Phys Chem Chem Phys) - "Our findings reveal that the NPPA analogues hold better chemical reactivity than the reference inhibitor (AZD5438) and are relatively electrophilic in nature...Additionally, it stabilizes the protein in dynamically stable conformations. These findings support the future development of novel CDK2 inhibitors by highlighting some crucial parameters underlying the activity of potent inhibitors."

Journal • Oncology

Design, synthesis, and biological evaluation of N-(2-amino-phenyl)-5-(4-aryl- pyrimidin-2-yl) amino)-1H-indole-2-carboxamide derivatives as novel inhibitors of CDK9 and class I HDACs for cancer treatment. (PubMed, Bioorg Chem) - "The cellular assays revealed that 13ea induced mitochondria-related apoptosis and G2/M phase arrest in cancer cells, showing superior activities compared to those of AZD-5438 (a CDK9 inhibitor) and Mocetinostat (an inhibitor of class I HDACs). Notably, the in vivo assay demonstrated that 13ea (30 mg/kg) exhibited significant inhibition on MDA-MB-231 xenograft tumor growth, with a tumor shrinkage rate of 76.83 %. In summary, we have identified 13ea as a novel CDK9/HDAC inhibitor with excellent anticancer activity in vitro and in vivo."

Journal • Oncology • CDK9 • HDAC1 • HDAC3

Efficacy of WNTinib, a novel selective therapeutic for CTNNB1-mutant tumors, in preclinical models of hepatoblastoma (EASL 2025) - "Standard perioperative platin-based regimens (e.g. cisplatin and doxorubicin) are associated with severe and lifelong side effects... To evaluate WNTinib efficacy, we performed 3 distinct animal models, including subcutaneous implantation of patient-derived xenograft (PDX) HB-tumors (n=6), or 5x10^6 immortalized (HepG2) and PDX-derived (TT001) HB cells in NSG mice (n=14/arm)... We have demonstrated that WNTinib effectively delays tumor progression and increases the overall survival in HB experimental models and identified DYRK1A kinase as a potential target to boost the efficacy of WNTinib activity in HB."

Preclinical • Hepatoblastoma • Hepatology • Oncology • Pediatrics • Rare Diseases • Solid Tumor • CTNNB1 • MAPK1

Discovery of new imidazole[1,2-a] pyridine derivatives as CDK9 inhibitors: design, synthesis and biological evaluation. (PubMed, RSC Med Chem) - "Moreover, compared with AZD5438, LB-1 demonstrated highly selective CDK9 inhibitory activity, with an IC50 value of 9.22 nM. Accordingly, compound LB-1 could be further developed as a selective, target-oriented CDK9 inhibitor for colorectal cancer."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Identification of C/EBPδ-Modifying Compounds as Potential Anticancer Agents Using a High-Throughput Drug Screen. (PubMed, J Cell Mol Med) - "We confirmed the potential importance of cell cycle-mediated regulation of C/EBPδ by showing that four of the most potent C/EBPδ activators-R547, PHA793387, AZD5438 and AT7519, all multi-cyclin-dependent kinase (CDK) inhibitors-limited the clonal expansion of PDAC cells. Next to providing a valuable selection of C/EBPδ-modulating compounds for the use in preclinical studies, this report contributes to our understanding of the molecular regulatory mechanisms of C/EBPδ in general and in PDAC in particular."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CEBPD

Machine learning-based integration develops a multiple programmed cell death signature for predicting the clinical outcome and drug sensitivity in colorectal cancer. (PubMed, Anticancer Drugs) - "In addition, the high-MPCDI group was more sensitive to AZD1332, Foretinib, and IGF1R_3801, and insensitive to AZD3759, AZD5438, AZD6482, Erlotinib, GSK591, IAP_5620, and Picolinici-acid, which suggests that the MPCDI can guide drug selection for CRC patients. As a new clinical classifier, the MPCDI can more accurately distinguish CRC patients who benefit from immunotherapy and develop personalized treatment strategies for CRC patients."

Clinical data • Journal • Machine learning • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss. (PubMed, Sci Adv) - "Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials."

Journal • Preclinical • Otorhinolaryngology • CDK2 • EGFR

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation. (PubMed, J Med Chem) - "In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a series of novel CDK9 inhibitors were rationally designed and synthesized based on the structure of AZD5438 (a pan CDKs inhibitor reported by AstraZeneca)...Research on the mechanism indicated that CLZX-205 could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression, and these results were validated at the cellular and tumor tissue levels. Currently, CLZX-205 is undergoing further research as a promising candidate for CRC treatment."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy. (PubMed, Bioorg Chem) - "Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC values of 0.83, 2.12, 3.12, and 8.61 μM, respectively, which were comparable to that of Palbociclib and AZD5438. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes."

Journal • Oncology • CCNA2 • CDK2

Identification of aneuploidy-related gene signature to predict survival in head and neck squamous cell carcinomas. (PubMed, Aging (Albany NY)) - "We classified 3 molecular subtypes for HNSC patients and established an ARS prognostic model, which offered a prospective direction for prognosis in HNSC."

Gene Signature • IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CCR4 • CCR7 • CD79A • ICOS • IL1R1 • ZAP70

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced Acute Kidney Injury. (PubMed, J Am Soc Nephrol) - "Cisplatin-induced damage to the inner ear and kidneys share similar cellular beneficial responses to AZD5438 and dabrafenib highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss."

Journal • Acute Kidney Injury • Nephrology • Oncology • Oral Cancer • Otorhinolaryngology • Renal Disease • Solid Tumor • PCNA

Optimization of a pyrazolopyridazine chemotype against Trypanosoma cruzi GSK-3β (ACS-Fall 2023) - "There are currently only two drugs that are used to treat Chagas Disease, nifurtimox and benznidazole, however, these are associated with toxicity and a lack of efficacy...Our lab originally identified AZD5438 as a potent inhibitor of T. brucei, L. infantum and T. cruzi...The main goals for further optimization are to (1) increase aqueous solubility and, (2) improve selectivity over human kinases while maintaining potency. These goals are not isolated from each other and are being considered simultaneously and a multiparameter optimization approach is being implemented to develop a lead compound within this series."

GSK3B

AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins. (PubMed, Sci Rep) - "To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential."

Journal • PPARGC1A