PIM447 / Novartis - LARVOL DELTA

PIM447, a Pan-PIM Kinase Inhibitor, in Combination with Venetoclax Exerts a Potent Anti-Tumor Activity in the Bone Marrow Niche (ASH 2024) - "Overall, our results demonstrated that PIM kinase inhibition (through the PIM447 compound) is a valuable tool for targeted AML therapy, exhibiting potent cytotoxic activity against AML cells. Notably, when combined with a BCL2 inhibitor, this strategy effectively overcomes the protective effect of the bone marrow microenvironment."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2L1 • FLT3 • MCL1 • NPM1

HGF Regulation in the Tumor-Supportive Microenvironment Combined with Pan-PIM Kinases Inhibition in Malignant Cells As a Multi-Target Approach for Acute Myeloid Leukemia (ASH 2023) - "A total of 5 healthy donors (HD) and 5 de novo AML patients BMMSC (CD90+CD105+CD73+CD45–CD34–CD31–HLA-DR–) were treated with 5-Azacitidine (Aza), and evaluated for SPINT2 gene expressions. Collectively, our data identify a novel pan-PIM kinase inhibitor, PIM447, which effectively induces leukemia cell apoptosis through reducing MET receptor activation as well as acts on their tumor-supportive microenvironment by inducing a phenotypic shift from immunosuppressive M2 to anti-tumor M1 macrophages. PIM447 also interplays with SPINT2/HGF pathway in the TME, reducing AML progression. These findings suggest that a pivotal strategy to treat AML could be a multi-target therapy, acting both on leukemia cells and in the tumor microenvironment."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD31 • CD34 • CD73 • CD80 • ENG • ITGA2 • ITGA4 • ITGA5 • MRC1 • PECAM1 • PIM1 • PIM3 • PTPRC • SPINT2 • THY1

Pim kinase inhibitor PIM447 enhances the anti-atherothrombotic properties of human coronary artery endothelial cells. (ISTH 2025) - "Using an endothelialised in vitro thrombosis model, TNFα mediated potentiation of thrombus formation on collagen were attenuated by PIM447, and releasate from PIM447 treated HCAECs was found to inhibit coagulation. PIM447 treatment was not found to affect HCAEC expression and release of Tissue Factor, thrombomodulin, PAI-1 or Antithrombin."

Cardiovascular • Hematological Disorders • Thrombosis • IL6 • PIM1 • TNFA

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

PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL. (PubMed, NPJ Precis Oncol) - "Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • T Acute Lymphoblastic Leukemia • MYC • PIM1

UM171 suppresses breast cancer progression by inducing KLF2. (PubMed, Breast Cancer Res Treat) - "These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer."

Journal • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Transplantation • Triple Negative Breast Cancer • CDKN1A • PIM1

PIM kinase inhibition synergizes with a MERTK inhibitor to treat osimertinib resistant EGFR-mutant non-small cell lung cancer (AACR 2024) - "Further, two structurally distinct PIM kinase inhibitors, SGI-1776 and PIM447, provided synergistic inhibition of cell expansion and colony formation in osimertinib-resistant cell line cultures when combined with MRX-2843 treatment. Furthermore, knockdown of PIM kinases (PIM1, 2, 3) using nine sets of siRNAs led to various changes in expression of TAM receptor family members (TYRO3, AXL, MERTK), indicating a role for PIM kinases in regulation of TAM kinase expression. These studies suggest a novel treatment strategy for osimertinib-resistant EGFR-mutant NSCLC using a first-in-class MERTK kinase inhibitor that is currently under evaluation in multiple Phase I clinical trials."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • EGFR • MERTK • PIM1

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

THERAPEUTIC POTENTIAL AND STRATEGIES OF PIM447, A PAN-PIM INHIBITOR, TARGETING REFRACTORY MYELOID LEUKEMIA WITH KIT-DRIVEN T(8/21) (EHA 2023) - "The cytotoxicity of PIM447 was detected in Kasumi-1 and SKNO-1 with IC 50 values of 1591.54 nM and 202.28 nM, respectively, indicating SKNO-1 cells responded well to PIM447. The IC 50 of 202.28 nM was much lower than plasma level of 3.1 μM, indicating the feasibility of PIM447 for subtype-specific clinical applications. Subsequent examination showed that PIM447 could induce cell cycle arrest in G 0 /G 1 phase while decreasing cyclin E protein content but increasing p27 protein content in SKNO-1 cells."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4EBP1 • KIT • PIM1 • STAT5

PAN-PIM KINASE INHIBITOR PIM447 SHOWS SUPERIOR ANTI-LEUKEMIC EFFECT IN ACUTE ERYTHROID LEUKEMIA (EHA 2023) - "PIM447 was effectively cytotoxic to acute erythroid leukemia cell line HEL92.1.7. Transcriptomic analysis and further experiments showed that PIM447 could suppress cell proliferation, induce cell cycle arrest, increase apoptosis, and damage mitochondria in HEL92.1.7 cells. In vivo xenograft model experiment demonstrated that PIM447 could retard HEL92.1.7 tumor growth."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4EBP1 • PIM1

Targeting BRD9 and PIM in prostate cancer (PROSCA-BLADDR 2022) - "PIM447 and I-BRD9 show promise as targeted therapies in PCa. There is insufficient evidence in this study to support further investigation of these inhibitors in combination."

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

Pim kinase: A novel regulator of platelet and megakaryocyte thromboxane A2 and C-X-C-R motif receptors (ISTH 2022) - " HEK293 cells transfected with Flag or GFP-tagged TPαR and MEG01 cells (expressing CXCR4) were treated with Pim kinase inhibitors (AZD1208, LGH447) for 10 minutes. No alteration in TxB2 generation indicates Pim kinase regulates platelet TxA2 receptor signalling independently of COX1 regulation. Pim kinase inhibition causes internalisation of both the CXCR4 and TPαR when assessed using flow cytometry and fluorescence microscopy. Consistent with the receptors being internalised, a reduction in TxA2 and SDF1a mediated calcium mobilisation, and phospho-PKC signalling was observed following treatment of platelets, HEK293 and MEG01 cells with Pim kinase inhibitors."

Cardiovascular • Hematological Disorders • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • Thrombosis • CXCL12 • PIM1

Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms. (PubMed, Clin Cancer Res) - "The triple combination of ruxolitinib, LEE011 and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in MPN patients."

Clinical • Journal • Fibrosis • Immunology • Myeloproliferative Neoplasm • Oncology • JAK1 • JAK2

PIM Kinases in Multiple Myeloma. (PubMed, Cancers (Basel)) - "The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials...Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted."

Journal • Review • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • PIM1

[VIRTUAL] PIM INHIBITORS INDUCE THE FERROPTOSIS VIA HIF1A/GPX4 PATHWAY IN HEMATOLOGICAL MALIGNANT CELLS (EHA 2021) - "Methods The cell lines SKM-1, MUTZ-3, THP-1, U266 and LP-1 treated with pim inhibitors (SMI-16a and Pim-447)...Conclusion Our study provides significant evidence to confirm the occurrence of ferroptosis in hematological malignant cells treated with pim inhibitors, and demonstrates that inhibition of ferroptosis was through HIF-1α/GPX4 pathway. These findings reveal a new form of cell death in the treatment of pim inhibitors."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • GPX4 • HIF1A

[VIRTUAL] A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor (AACR 2021) - "Furthermore, treatment with PIM447, a structurally distinct PIM kinase inhibitor, and MRX-2843 decreased cell expansion more effectively than either agent alone. Additionally, combined treatment with MRX-2843 and SGI-1776 prevented colony formation, while single agents had limited effect. In all, these data indicate that combining MRX-2843 and a PIM TKI may control osimertinib resistant tumor growth, providing a potential treatment strategy for osimertinib resistant EGFR-mutated NSCLC patients for whom the choices are still limited."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MERTK

PIM447 inhibits oncogenesis and potentiates cisplatin effects in hepatoblastoma. (PubMed, J Pediatr Surg) - "We showed that PIM447 inhibits oncogenesis and potentiates the effects of cisplatin in hepatoblastoma and, therefore, warrants further investigation as a potential therapeutic agent for hepatoblastoma."

Journal • Gastrointestinal Cancer • Hematological Malignancies • Hepatoblastoma • Hepatology • Oncology • Solid Tumor • CD133

A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma. (PubMed, Int J Hematol) - P1 | "PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951)."

Clinical • Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Multiple Myeloma • Oncology • Thrombocytopenia

Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Myelofibrosis • JAK2 • MRI

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma. (PubMed, Cancers (Basel)) - "Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma."

Combination therapy • Journal • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • EIF4E • IRF4 • MYC

Rethinking Risk-Benefit Assessment for Phase I Multiple Myeloma Trials (ASH 2016) - "Daratumuab, ixazomib, pomalidomide, Isatuximab, marizomib, oprozomib, filanesib, dinaciclib, venetoclax and LGH-447, had single agent anti-myeloma activity and proceeded to later phase clinical trials (Fig. Four new therapeutic agents, panobinostat, daratumumab, elotuzumab, and ixazomib were approved in 2015 matching the record of seven new-agents and 16 regulatory approvals during the past 12 years."

Adverse events • Combination therapy • Biosimilar • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] PIM Kinase Inhibitor, PIM447, Decreases Oncogenicity and Cancer Cell Stemness in a Human Hepatoblastoma Patient-Derived Xenograft (ACS-CLINCON 2020) - "PIM447 decreased hepatoblastoma PDX cell survival, proliferation, and motility. Further, PIM447 significantly diminished the stem cell phenotype of COA67 cells. These data provide evidence that PIM447 warrants further exploration as a therapeutic agent for hepatoblastoma."

Clinical • Gastrointestinal Cancer • Hematological Malignancies • Hepatoblastoma • Hepatology • Leukemia • Oncology • Solid Tumor • CD133

Anti-tumour effects of PIM kinase inhibition on progression and chemoresistance of hepatocellular carcinoma. (PubMed, J Pathol) - "Our findings demonstrate that PIM inhibitors SGI-1776 and PIM447 reduced HCC proliferation, metastatic potential, and self-renewal in vitro. Results from in vivo experiments supported the role of PIM inhibition in suppressing of tumour growth and increasing chemosensitivity of HCC toward cisplatin and doxorubicin, the two commonly used chemotherapeutic agents in trans-arterial chemoembolisation (TACE) for HCC...Taken together, PIM inhibitors demonstrated remarkable anti-tumourigenic effects in HCC in vitro and in vivo. PIM kinase inhibition is a potential approach to be exploited in formulating adjuvant therapy for HCC patients of different disease stages."

Journal • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Liver Cancer • Oncology • Solid Tumor • ICAM1

Synergistic Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms (ASH 2016) - "Using INC424 (JAK1/2 inhibitor ruxolitinib), PIM447 (pan-PIM inhibitor), and LEE011 (CDK4/6 inhibitor) we first sought to determine the effect of combination therapy with INC424 and PIM447 or INC424 and LEE011 compared with monotherapy in allografted Ba/f3 cells expressing EPOR-JAK2V617F. Further studies are ongoing to evaluate the ability of this therapeutic strategy to reduce disease initiating capacity and disease progression. This combination represents a promising therapeutic strategy presently under evaluation in a Phase I clinical study."

Combination therapy • Acute Myelogenous Leukemia • Biosimilar • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Ophthalmology • Venous Thromboembolism

The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and/or refractory multiple myeloma. (PubMed, Leukemia) - "Median progression-free survival at the RD was 10.9 months. PIM447 was well tolerated and demonstrated single-agent antitumor activity in relapsed/refractory MM patients, providing proof of principle for Pim (Proviral Insertions of Moloney Murine leukemia virus) kinase inhibition as a novel therapeutic approach in MM."

Clinical • Journal • P1 data • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology