saracatinib (AZD0530) / AstraZeneca - LARVOL DELTA

CT7439 an oral first-in class selective CDK12 and 13 inhibitor and cyclin K degrader: Profiling activity and combination efficacy in an ovarian cancer model (AACR 2025) - "CT7439 activity in OV-90 in cellular assays:OV-90GrowthCCNK**BRAC1*ERCC4*RAD51C*POLQ*MCL-1*IC50 nM (SD)4.40.66 (0.1)1.7 (0.4)0.82(0.3)1.2 (0.7)1.9(0.2)>20Data is mean ± SD (**Western blot, *qPCR) In addition to single agent activity of CT7439 a strong combination activity between CT7439 and the PARP inhibitors Olaparib, Niraparib and AZD10530 as well as the carboplatin was observed in an OV-90 cellular confluency assay. CT7439 is an orally bioavailable selective CDK12/13 inhibitor and degrader of CCNK. Pre-clinical studies demonstrates clinical potential for monotherapy use in solid tumors and as a combination therapy with agents known to cause a DNA damage response."

Clinical • Preclinical • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • CDK12 • CDK13 • ERCC4 • MCL1 • POLQ • RAD51C

High-throughput screening identifies bazedoxifene as a potential therapeutic for dysferlin-deficient limb girdle muscular dystrophy. (PubMed, Br J Pharmacol) - "Our drug screening identified saracatinib and bazedoxifene as potential treatments for LGMD R2, especially for patients with the L1341P mutation. The widespread protective effect of bazedoxifene reveals a new avenue toward genotype-independent treatment of LGMD R2 patients."

Journal • Genetic Disorders • Muscular Dystrophy

The IGF2BP1 oncogene is a druggable m6A-dependent enhancer of YAP1-driven gene expression in ovarian cancer. (PubMed, NAR Cancer) - "In contrast, SRC inhibition with Saracatinib fails to inhibit YAP1/TAZ-driven transcription and cell growth in general...In such invasive carcinoma models, the combined inhibition of SRC, IGF2BP1, and YAP1/TAZ proved superior over monotherapies. These findings highlight the therapeutic potential of targeting IGF2BP1, a key regulator of oncogenic transcription networks."

Journal • Oncology • Ovarian Cancer • Solid Tumor • IGF2 • IGF2BP1 • YAP1

Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt. (PubMed, PLoS Pathog) - "Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis."

Journal • Infectious Disease • BECN1 • LAMP1 • PTEN

IGF2BP3 Triggers STAT3 Pathway by Stabilizing SRC RNA in an m6A-Dependent Manner to Promote Lymphatic Metastasis in LUAD. (PubMed, Cancer Sci) - "The cell migration and EMT function of IGF2BP3 were partially rescued by utilizing SRC siRNA or AZD0530, an SRC inhibitor. This study demonstrated that IGF2BP3 promotes lymphatic metastasis in LUAD via activating the m6A-SRC-STAT3-VEGFC signaling axis, indicating that IGF2BP3 is a potential therapeutic target to overcome metastasis in LUAD patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IGF2BP3 • VEGFC

A Novel Prognostic Risk Model Based on Oxidative Stress to Predict Survival and Improve Treatment Strategies in Stomach Adenocarcinoma. (PubMed, Comb Chem High Throughput Screen) - "Our study has effectively established an oxidative stress-related prognostic model, providing a promising tool for personalized clinical strategies and improved STAD patient outcomes."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • ADCYAP1 • ANXA5 • CD36 • NOS3 • SCARB1 • SERPINE1

Drug Development. (PubMed, Alzheimers Dement) - "We have successfully evaluated previously reported inhibitors and introduced a novel type II Lyn kinase inhibitor with picomolar (pM) activities suitable for use as chemical probes to investigate the role of Lyn in TREM2-mediated microglial activation."

Journal • Alzheimer's Disease • CNS Disorders • LYN

A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer (clinicaltrials.gov) - P1/2 | N=71 | Completed | Sponsor: Joyce Marie Slingerland, MD | Phase classification: P2 ➔ P1/2

Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Mesothelin Promotes Acute Myeloid Leukemia Cell Proliferation, Adhesion, and Chemoresistance through Novel Binding Partner Lyn (ASH 2024) - "To investigate the role of Lyn in MSLN-induced resistance to Ara-C, we used saracatinib (pan-SFK inhibitor) and bafetinib (Lyn inhibitor) in conjunction with Ara-C. Taken together, our data support MSLN playing an oncogenic role through increased proliferation, cell cycle progression, metabolic fitness, ECM adhesion, and Ara-C resistance. We identified a novel MSLN-Lyn signaling axis that could be used to improve targeted therapy approaches."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • LYN • MSLN • MUC16

Exploration on the construction of a bladder cancer prognostic model based on disulfidptosis-related lncRNAs and its clinical significance. (PubMed, Sci Rep) - "Lastly, the drug sensitivity analysis revealed that the BLCA cells in the high-risk group showed an increased sensitivity to cisplatin, sunitinib, cetuximab, axitinib, docetaxel, saracatinib, vinblastine and pazopanib compared with those in the low-risk group. According to the Quantitative real time PCR results, we found that five lncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line. The disulfidptosis-related lncRNA risk model has a valuable effect in assessing the prognosis of BLCA patients."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • TMB

A Multi-Omics Prognostic Model Capturing Tumor Stemness and the Immune Microenvironment in Clear Cell Renal Cell Carcinoma. (PubMed, Biomedicines) - "The CRCS2 subtype was in a hypoxic state and was characterized by suppression and exclusion of immune function, which was sensitive to gefitinib, erlotinib, and saracatinib. Our findings highlight the key role of CSCs in shaping the ccRCC tumor microenvironment, crucial for therapy research and clinical guidance. Recognizing tumor stemness helps to predict treatment efficacy, recurrence, and drug resistance, informing treatment strategies and enhancing ccRCC patient outcomes."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • SAA2

Validation of a functional human AD model with four AD therapeutics utilizing patterned ipsc-derived cortical neurons integrated with microelectrode arrays. (PubMed, Sci Rep) - "LTP was induced by tetanic electrical stimulation, and LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42-induced LTP impairment. The results illustrate the utility of the system as a validated platform to model MCI AD pathology, and potentially for the pre-MCI phase before significant neuronal death. This system also has the potential to become an ideal platform for high-content therapeutic screening for other neurodegenerative diseases."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Aβ42

Histones in extracellular vesicles amplify NLRP3-inflammasome activation and alpha-synuclein aggregation in environmentally linked Parkinson's disease (Neuroscience 2024) - "The Fyn inhibitor saracatinib, or Fyn knockdown, dampened H3-mediated NLRP3 inflammasome activation, suggesting the involvement of Fyn kinase in this process. Interestingly, we found rH3 interacted with monomeric α-syn, augmenting its aggregation, suggesting that H3 can serve as a possible co-factor regulating the pathogenic α-syn protein misfolding process. Collectively, these results demonstrate that H3 in EVs may serve as a key pro-inflammatory amplifier of α-syn protein aggregation and neuroinflammation through the activation of NLRP3 inflammasome signaling via Fyn kinase signaling."

Late-breaking abstract • CNS Disorders • Parkinson's Disease • IL18 • IL1B • NLRP3

Gender-different effect of Src family kinases antagonism on photophobia and trigeminal ganglion activity. (PubMed, J Headache Pain) - "In conclusion, our data revealed that SFKs antagonism reduced photophobia processing in male mice and exhibited gender-different modulation of trigeminal ganglion activity, primarily manifesting as alterations in the transcriptome profile. These findings underscore the potential of SFKs antagonism for allieving photophobia in males, highlighting its value in the emerging field of precision medicine."

Journal • CNS Disorders • Migraine • Pain • ADCYAP1 • AKT1 • CREBBP • SCN8A • TRPA1 • TRPM3 • ZMYND8

Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy. (PubMed, Brain Commun) - "The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy."

Journal • Alzheimer's Disease • CNS Disorders • Epilepsy • DLG4

Construction of a prognostic model for colon cancer by combining endoplasmic reticulum stress responsive genes. (PubMed, J Proteomics) - "Finally, based on the cMAP database, we identified several potential drugs that could target high-risk groups, such as Dasatinib, GNF-2, Saracatinib, and WZ-1-84. This model can be used as a predictor of prognosis and immunotherapy response in colon cancer patients. At the same time, model-based prediction of drugs can also be a potential option for colon cancer treatment in the future."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EIF4A1 • GRIN2B • IRX3 • LRRC59 • NTRK2 • XBP1

Follow-up STOPFOP: A Phase II Clinical Trial to Prevent Heterotopic Ossification in FOP Using Saracatinib (AZD0530) (ASBMR 2024) - No abstract available

Clinical • P2 data • Growth Hormone Deficiency (Adult) • Orthopedics

Identification of Chemical Tool Compounds to Investigate the Role of Lyn Kinase in TREM2-Mediated Microglia Activation and Phagocytosis (AAIC 2024) - " Our findings revealed that Type I inhibitors, particularly Saracatinib and Bosutinib, potently inhibit Lyn within the picomolar (pM) range. On the other hand, Type II inhibitors, such as Masitinib and Imatinib, displayed pronounced >20-fold selectivity for Lyn over Hck with low nM Lyn inhibitor activities... We have successfully evaluated previously reported inhibitors and introduced a novel type II Lyn kinase inhibitor with picomolar (pM) activities suitable for use as chemical probes to investigate the role of Lyn in TREM2-mediated microglial activation."

Alzheimer's Disease • CNS Disorders • LYN

EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma. (PubMed, Int J Mol Sci) - "Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • JAK1 • STAT5 • STAT5AWqe • STAT5B

Identification of a Macrophage marker gene signature to evaluate immune infiltration and therapeutic response in hepatocellular carcinoma. (PubMed, Heliyon) - "Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244. A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients."

Gene Signature • IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • LAG3 • PD-1 • TIGIT

Cigarette Smoke Acts Via c-Src to Decrease CXCL11 Levels and Deter Lung Treg Responses in HIV-related COPD (ATS 2024) - "Cigarette smoke increased lung c-Src activity in mice and the c-Src inhibitor AZD0530 restored Cxcl11 expression in smoke exposed mice and alveolar macrophages... Cigarette smoke activates c-Src to suppress CXCL11 levels thereby diminishing lung Treg responses that counter airways disease and lung tissue destruction in HIV-infected individuals."

Chronic Obstructive Pulmonary Disease • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL11 • ELANE

Low concentrations of saracatinib promote definitive endoderm differentiation through inhibition of FAK-YAP signaling axis. (PubMed, Cell Commun Signal) - "For induction of the pancreatic lineage, 10 ng/ml AA combined with SAR at the DE differentiation stage yielded a comparative number of PDX1+/NKX6.1+ pancreatic progenitor cells to those obtained by 50 ng/ml AA treatment. Our study highlights SAR as a potential modulator that facilitates the cost-effective generation of DE cells and provides insight into the orchestration of cell fate determination."

Journal • PDX1 • PTK2

Ex Vivo Testing of Antifibrotic Drugs in a Long-term Culture of Precision-cut Lung Slices (PCLS) (ATS 2024) - " In this study, freshly acquired IPF lung explants (n=20) were embedded in agarose, sliced into 300 µm-thick sections using a vibrating microtome, and cultured in 24-well plates with TGF-β, pan-ALK-inhibitor (SB431542), saracatinib, nintedanib and pirfenidone. Our novel long-term PCLS culture method using IPF tissue enables meaningful ex vivo testing of anti-fibrotic drug effects for the first time. Remarkably, fibrosis and tissue remodeling in IPF tissue continued to advance during the cultivation period. This approach holds promise for advancing our understanding of IPF and developing more effective treatments."

Preclinical • Fibrosis • CTGF • TGFB1

STOPFOP: Saracatinib Trial TO Prevent FOP (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Amsterdam UMC, location VUmc | Trial completion date: Aug 2024 ➔ May 2025 | Trial primary completion date: Aug 2024 ➔ May 2025

Trial completion date • Trial primary completion date

Dual Drug Repurposing: The Example of Saracatinib. (PubMed, Int J Mol Sci) - "In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases."

Journal • Review • Alzheimer's Disease • CNS Disorders • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Oncology • Pain