AZD1208 / AstraZeneca - LARVOL DELTA

Novel Autoregulation of PIM2 Expression Sustains Plasma Cell Survival in Multiple Myeloma (IMMUNOLOGY 2025) - "Using PIM2-selective inhibitors, JP11646 (targeting both functions), CpdA (kinase-independent), and AZD1208 (kinase-dependent), we show a novel PIM2 autoregulatory paradigm. Our findings reveal that PIM2 maintains its own expression through kinase-independent transcriptional control while promoting cell survival through kinase-dependent pathways, establishing a novel circuit in malignant plasma cells. This work provides fundamental insights into immune cell gene regulation and suggests innovative therapeutic strategies targeting the dual functions of PIM2 in MM.Keywords: Cells B Cells; Molecules Protein Kinases/Phosphatases Transcription Factors; Processes Gene Regulation; Techniques/Approaches Molecular Biology"

Hematological Malignancies • Multiple Myeloma • Oncology • PIM2

Valosin-Containing Protein (VCP/p97) Mediates Neuroendocrine Differentiation in Prostate Cancer Cells Through Pim1 Signaling Inducing Autophagy. (PubMed, Prostate) - "VCP drives NED in PCa cells through a complex interplay involving the Pim1 axis and autophagy pathways. These findings highlight the potential of targeting VCP/p97 and its associated mechanisms as therapeutic strategies to inhibit NED progression."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • IL6 • MYC • PIM1 • SQSTM1 • STK11 • VCP

Dual Targeting of Pim and PI3 Kinases in Mature T-Cell Lymphoma. (PubMed, Eur J Haematol) - "Strikingly, IBL-202 strongly induced cell-cycle-dependent cell death in cell lines of different mTCL subtypes. Together, our study provides mechanistic evidence supporting a therapeutic strategy of dual Pim- and PI3-kinase inhibition in mature T-cell lymphoma."

Journal • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2L1

Targeting of PIM Kinases Shows Single Agent Efficacy and Synergizes With BCL2 Inhibitors in Diffuse Large B Cell Lymphoma of the ABC Subtype. (PubMed, Hematol Oncol) - "The combination of AZD1208 with the clinically available BCL2 inhibitor venetoclax was synergistic in most DLBCL cell lines, and this combination induced apoptosis and reduced levels of AKT and MCL1 proteins. These combinations may enable lower doses of PIM inhibitors, leading to increased tolerability and improved anti-tumor activity in clinical settings. The study also highlighted the potential for targeting PIM kinases in combination with other therapies to overcome drug resistance in DLBCL."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MCL1 • PIM1

Unraveling the Kinase-Independent Autoregulatory Mechanism of PIM2 in Multiple Myeloma (ASH 2024) - "While ATP-competitive PIM2 kinase inhibitors have shown limited efficacy in clinical trials, our laboratory has recently developed and reported on JP11646 (JP1), a first-in-class PIM2-selective non-ATP competitive inhibitor (JR Nair, 2017)...PIM2 promoter activity was measured using luciferase assays with PIM2 Ki inhibitors (JP1, JP2) and a kinase-dependent (Kdep) inhibitor (AZD1208)...SP1 inhibition with terameprocol (TMP) decreased PIM2 protein levels, as shown by Western blot analysis...The identification of specific regulatory elements governing PIM2 Ki autoregulation reveals a new vulnerability in MM that may be exploited for treatment. Further investigation of this complex regulatory network may lead to innovative strategies for targeting PIM2 overexpression in MM therapy."

Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation • MYC • PIM1 • PIM3

PIM1 inhibition: a novel therapeutic approach for IDH-mutant gliomas (SNO 2024) - "A pan-PIM inhibitor, AZD1208 significantly suppressed cell viability, cell proliferation, and colony formation in IDH-mutant cells but had a lesser effect in IDH-wildtype cells... m6A RNA modification contributes to an enhanced PIM1 activity and thereby a selective sensitivity to PIM1 inhibition in IDH-mutant gliomas."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • FTO • YTHDF1

PIM1 inhibition: a novel therapeutic approach for IDH-mutant gliomas (SNO 2024) - "A pan-PIM inhibitor, AZD1208 significantly suppressed cell viability, cell proliferation, and colony formation in IDH-mutant cells but had a lesser effect in IDH-wildtype cells... m6A RNA modification contributes to an enhanced PIM1 activity and thereby a selective sensitivity to PIM1 inhibition in IDH-mutant gliomas."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • FTO • YTHDF1

Elucidating the Kinase-Independent Autoregulatory Loop of PIM2 in Multiple Myeloma (IMW 2024) - "Luciferase assays were performed using the full-length PIM2 promoter to assess transcriptional activity in response to PIM2 Ki inhibitors (JP1 and JP2) and a PIM2 kinase-dependent (Kdep) inhibitor (AZD1208)... Our preliminary data support the hypothesis of a novel PIM2 kinase-independent autoregulatory mechanism involving MYC and SP1 in MM. Disruption of this potential PIM2 Ki autoregulatory loop using selective inhibitors (JP1 and JP2) decreases PIM2 expression and promoter activity, suggesting it as a potential therapeutic target. Further investigation into the specific cis-regulatory elements and binding sites governing PIM2 Ki autoregulation may uncover new vulnerabilities to exploit in MM treatment."

Hematological Malignancies • Multiple Myeloma • Oncology

PIM Kinase Inhibitors as Novel Promising Therapeutic Scaffolds in Cancer Therapy. (PubMed, Curr Top Med Chem) - "A few small chemical inhibitors (E.g., SGI-1776, AZD1208, LGH447) that specifically target the PIM proteins' adenosine triphosphate (ATP)-binding domain have been identified. We explore the involvement of oncogenic transcription factor c-Mycandmi-RNA in relation to PIM kinase. In this article, we highlight the oncogenic effects, and structural insights into PIM kinase inhibitors for the treatment of cancer."

Journal • Hematological Malignancies • Leukemia • Oncology • PIM1

Inhibition of Pim kinases triggers a broad antiviral activity by affecting innate immunity and via the PI3K-Akt-mTOR axis the endolysosomal system. (PubMed, Antiviral Res) - "The pan-Pim kinase inhibitor AZD1208 exerted an extraordinarily high antiviral effect against various ZIKV isolates, SARS-CoV-2) and HBV...We identified Pim-kinases as cellular target for a broad antiviral activity. The antiviral effect exerted by inhibition of Pim-kinases is based on at least two pillars: innate immunity and modulation of the endolysosomal system."

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • FGFR1

Optical coherence tomography for multicellular tumor spheroid category recognition and drug screening classification via multi-spatial-superficial-parameter and machine learning. (PubMed, Biomed Opt Express) - "Our results indicated that the effective features combined with supervised learning models successfully classify OVCAR-8 MCTS culturing with 5,000 and 50,000 cell numbers, MCTS with pancreatic tumor cells (Panc02-H7) culturing with the ratio of 0%, 33%, 50%, and 67% of fibroblasts, and OVCAR-4 MCTS treated by 2-methoxyestradiol, AZD1208, and R-ketorolac with concentrations of 1, 10, and 25 µM. This approach holds promise for obtaining multi-dimensional physiological and functional evaluations for using OCT and MCTS in anticancer studies."

Journal • Machine learning • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

First reported PIM kinase degraders: Design, profiling & optimization (AACR 2024) - "The first generation of PIM inhibitors to make it to the clinic, including SGI-1776, AZD1208 and PIM447, are known to be pan-PIM inhibitors, while the aim of this project was to identify novel & selective PIM3 inhibitors. This comprehensive screening cascade ensures an in-depth characterization and optimization of protein degraders, with the possibility of monitoring the ternary complex formation with biophysics methods. It is a good illustration of how this combination of tests can be instrumental in selecting the best degraders to progress to the next step of drug discovery."

Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • CRBN • DDB1 • FLT3 • JAK2 • PIM1 • PIM3

Prognostic Model Construction of Disulfidptosis-Related Genes and Targeted Anticancer Drug Research in Pancreatic Cancer. (PubMed, Mol Biotechnol) - "Furthermore, through computational biology approaches, the drug AZD1208 was identified as a potential treatment targeting the PPARG protein for pancreatic cancer. This discovery opens new avenues for exploring targets and screening drugs for pancreatic cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • PPARG

PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin. (PubMed, J Pediatr Surg) - "The correlation between PIM and ABCC1 gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • ABCC1 • PIM1 • PIM3

Pim kinase inhibitors increase gilteritinib cytotoxicity in FLT3-ITD acute myeloid leukemia through GSK-3β activation and c-Myc and Mcl-1 proteasomal degradation. (PubMed, Cancer Res Commun) - "Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  ."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • MCL1 • MYC • PIM1 • STAT5

PIM kinase inhibitor AZD1208 in conjunction with Th1 cytokines potentiate death of breast cancer cellsin vitrowhile also maximizing suppression of tumor growthin vivo when combined with immunotherapy. (PubMed, Cell Immunol) - "Nonetheless, when multiplexed therapies were tested in a murine model of HER-2 breast cancer, combinations of HER-2 peptide-pulsed DCs and AZD1208, as well as recombinant IFN-γ plus AZD1208 significantly suppressed tumor outgrowth compared with single-treatment and control groups. These studies suggest that PIM antagonism may combine productively with certain immunotherapies to improve responsiveness."

IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • IFNG • TNFA

PIM Kinase Inhibition Attenuates the Malignant Progression of Metastatic Hepatoblastoma. (PubMed, Int J Mol Sci) - "PIM kinase inhibition was attained using PIM3 siRNA and the pan-PIM inhibitor, AZD1208. When assessing the combined effects of pharmacologic PIM kinase inhibition with cisplatin on HLM_2 cells, we found the agents to be synergistic, potentially through inhibition of the ATM pathway. These findings support further exploration of PIM kinase inhibition as a therapeutic strategy for metastatic hepatoblastoma."

Journal • Metastases • Ataxia • Gastrointestinal Cancer • Hepatoblastoma • Hepatology • Immunology • Liver Cancer • Movement Disorders • Oncology • Pediatrics • Primary Immunodeficiency • Solid Tumor • CDKN1A

PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation. (PubMed, Cell Signal) - "PIM1 inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Renal Disease • PIM1

Pim Kinase Inhibition Halts the Malignant Progression of Metastatic Hepatoblastoma (ACS-CLINCON 2023) - "Effects of AZD1208, a pan-PIM inhibitor, on proliferation were determined via growth curve. PIM kinase inhibition decreased viability and proliferation in metastatic hepatoblastoma cells. Cell cycle progression was diminished, likely through dephosphorylation of p21. Combining PIM inhibition with cisplatin resulted in a synergistic response."

Metastases • Gastrointestinal Cancer • Hepatoblastoma • Hepatology • Oncology • Pediatrics • Solid Tumor • CDKN1A • PIM1

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500 nM) or HS38. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor."

Journal • Benign Prostatic Hyperplasia • PIM1

Inhibition of ErbB3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival. (PubMed, Am J Pathol) - "Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, calmodulin) and parallel (AZD1208) signaling pathways involving MAPK and mTOR reduced MPNST proliferation and survival. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events and when combined with trifluoperazine even more effectively reduces proliferation and survival compared to monotherapy. Our findings implicate erbB3, calmodulin, PIM kinases and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective."

Journal • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • ERBB3 • NRG1

NATURAL FLAVONOIDS INHIBIT MYELOID NEOPLASM PROLIFERATION BY REGULATING PIM2 KINASE ACTIVITY (EHA 2023) - "Kaempferol and Quercetin Dihydrate inhibit proliferation and induce apoptosis of myeloid neoplasms cells. PIM2 is an important target for the development and prognosis of acute myeloid leukemia and MDS. Kaempferol and Quercetin Dihydrate inhibit PIM2 kinase in myeloid neoplasms cells and subsequently participate in NF-κB expression, proliferation and regulation of myeloid neoplasms."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BAX • BCL2 • CASP3 • GLI2 • NF-κβ • PIM1 • PIM3

SCREEN: Spatial transcriptomic effects of a panel of pre-clinical and clinical targeted therapeutic combinations in a clinically relevant prostate explant model (EACR 2023) - "These drugs were AZD-1208, a pan-PIM kinase inhibitor; BEZ235/Dactolisib, a pan-PI3K-mTOR dual inhibitor, a combination of both AZD-1208 and BEZ235, and AUM-302 – a preclinical PIM, PI3K, mTOR triple inhibitor. However, AZD-1208 activated PI3K cascade. MKi67 and PIM genes activity switched between different cell types in response to the different treatments, which may be compensatory.ConclusionWe conclude that pre-clinical drug development can and should be carried out not just on cancer cells but on complex models, including epithelium, stroma, and benign areas, and that when such drug screening is carried out, advanced endpoint analyses such as spatial transcriptomics are warranted, in order to properly assess both the promise and the pitfalls of drug candidates in clinically relevant settings."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PIM1

PIM kinases are essential for CD8 T cell effector function and metabolism during chronic viral infection (P727) (IMMUNOLOGY 2023) - "In addition, pharmacological inhibition of PIM kinases with AZD1208, a pan-PIM kinase inhibitor, in activated CD8 T cells results in compromised mitochondrial metabolism, which is essential for effector CD8 T cell function. Overall, our results suggest that PIM kinases are critical for effector CD8 T cell differentiation, function, and metabolism in the control of chronic viral infection."

Late-breaking abstract • CNS Disorders • Infectious Disease • CD4 • CD8 • IL21 • PIM1

Optical Coherence Tomography of Tumor Spheroids Identifies Candidates for Drug Repurposing in Ovarian Cancer. (PubMed, IEEE Trans Biomed Eng) - "Our results indicated that OCT was capable and reliable to monitor the therapeutic effect of inhibitors to ovarian MCTs and it can be used for the rapid characterization of novel therapeutics for ovarian cancers in the future."

Journal • Oncology • Ovarian Cancer • Solid Tumor