JP_11646 / Jasco - LARVOL DELTA

PIM2-dependent modulation of mitochondrial mass and function in multiple myeloma (ASH 2025) - "We hypothesize that PIM2 has anunexplored role in modulating mitochondrial biogenesis to maintain survival of MM cells.We employed PIM2 molecular manipulation: overexpression (OE) of wild type (WT) or kinase dead (K61A)and knockdown (with siRNA or doxycycline-inducible shRNA-ishPIM2) as well as pharmacologicalinhibition of PIM2 protein level and activity, in MM cell lines...LoweringPIM2 protein expression (JP11646; 30 mg/kg by oral gavage) in Vk*myc tail vein injected mouse myelomamodel significantly decreased disease progression in as little as 21 days, while AZD1208 treatment wasnot significantly changing mouse IgG levels when compared with vehicle treatment...Together, these results suggest a KI role of PIM2, in mitochondria biogenesis.Moreover, the anti-survival effects resulted from PIM2 protein degradation in MM cells, might be partiallyattributed to inhibition of mitochondrial biogenesis. Thus, what sustains the functionality and metabolicintegrity of MM..."

IO biomarker • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Targeted Protein Degradation • LONP1 • MYC • NRF1 • PIM2 • PPARGC1A • TFAM

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

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

PIM2 supports survival of multiple myeloma cells by modulating mitochondrial biogenesis (IMMUNOLOGY 2025) - "Lowering PIM2 protein expression (JP11646, Cpd A and knockdown) but not kinase only inhibition (Cpd B), significantly reduced mtDNA-CN, mitochondrial mass and function (OCR) and the expression of key nuclear mitochondrial biogenesis genes, targets of c-Myc target genes (TFAM, PGC1a and LonP1). ChIP-seq analysis showed a PIM2 KI occupancy of PIM2 and MRPS10 promoters. These results support a KI role of PIM2 in modulating mitochondria biogenesis in MM and its importance as a therapeutic target for curative treatment approaches.Keywords: Animals Human; Cells B Cells; Molecules Protein Kinases/Phosphatases; Processes Cell Proliferation; Techniques/Approaches Molecular Biology"

Hematological Malignancies • Multiple Myeloma • Oncology • LONP1 • MYC • PIM2 • PPARGC1A • TFAM

Targeting pro-survival MYC oncogene expression in small cell lung cancer and large cell neuroendocrine carcinoma of the lung with a novel small molecule PIM2 inhibitor (AACR 2025) - "Given the observed reduction of PIM2 protein levels following treatment, we hypothesize that JP11646 functions through a feedback mechanism, disrupting PIM2:MYC interactions to reduce MYC paralog RNA/protein expression in lung NECs and exert its anticancer effects. Future studies are underway to further examine the mechanism and preclinical effects of JP11646, including xenograft studies, proteasome inhibitor studies, and CRISPR knockout of PIM2."

Breast Cancer • Endocrine Cancer • Hematological Malignancies • Large Cell Carcinoma • Lung Cancer • Multiple Myeloma • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • AURKA • MYC • PIM2

JP11646-mediated PIM2 Inhibition Has Potent Antitumor Effects in Small Cell Lung Cancer and Large Cell Neuroendocrine Carcinoma of the Lung (IASLC-WCLC 2024) - "JP11646 leads to reductions in MYC paralogs. Validation with xenograft models and exploration of the downstream effectors of MYC with JP11646 are planned."

Endocrine Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MYC • MYCN • VCL

Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors. (PubMed, Int J Oncol) - "By contrast, another pan‑PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome‑dependent...JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers."

Journal • Breast Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • Targeted Protein Degradation

Targeting Pim2 for Improving T-Cell Effector Function and Promoting Cancer Immunotherapy (ASH 2021) - "To further evaluate the clinical translation potential, we applied a Pim2-specific inhibitor (JP11646) and found that blocking Pim2 improved graft-versus-leukemia activity after autologous HCT and also enhanced CD8 T-cell mediated anti-melanoma effects after ACT in mice (Figure B, C)...Our work demonstrated that Pim2 is a potent and distinct regulator of differentiation and maintenance of T effector cells through modulating metabolism and autophagy. Specifically target Pim2 can serve as a novel strategy for improving cancer immunotherapy."

IO biomarker • Breast Cancer • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor • Transplantation • CD19 • CD8 • PIM1 • PIM2 • SELL