CINelim (terameprocol) / Erimos Pharma - LARVOL DELTA

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

Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling. (PubMed, Cancers (Basel)) - "Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • BCL2 • BIRC5 • CASP3 • CDK1 • CDKN1A

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR). (PubMed, Cell Rep Med) - P1 | "These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794)."

Journal • P1 data • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets. (PubMed, PLoS One) - "Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells...Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer."

Journal • Preclinical • Brain Cancer • CNS Tumor • Genetic Disorders • Glioblastoma • Obesity • Oncology • Solid Tumor • ATF4 • HIF1A • LDHA • NAMPT • TCF4

Quantitation of terameprocol in human plasma by liquid chromatography-tandem mass spectrometry. (PubMed, J Pharm Biomed Anal) - "Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time...Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor

[VIRTUAL] Mature osteoblasts induce myeloma cell death through inhibiting the Sp1‐TAK1‐Pim2‐prosurvival pathway (BSH-I 2020) - "Importantly, the Sp1 inhibitor, terameprocol, induced MM cell death along with reduction of TAK1, Pim-2, IRF4 and cMyc...Furthermore, the AMPK activator, AICAR, triggered MM cell death; the AMPK inhibitor, dorsomorphin, partially mitigated the OB-induced MM cell death, suggesting further impairment of MM cells by AMPK activation. Conclusions In sharp contrast to MM growth enhancement with activation of the TAK1-Pim-2 pathway by BMSCs and osteoclasts, OBs with mineralized nodule formation are able to induce apoptosis along with inhibition of the Sp1-TAK1-Pim-2-mediated prosurvival pathways and thereby impairing PGC-1a-driven energy production and metabolism."

Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation • CASP8 • DKK1 • IRF4 • MYC

Mature osteoblasts induce myeloma cell death through inhibiting the Sp1‐TAK1‐Pim2‐prosurvival pathway (BSH 2020) - "Importantly, the Sp1 inhibitor, terameprocol, induced MM cell death along with reduction of TAK1, Pim-2, IRF4 and cMyc...Furthermore, the AMPK activator, AICAR, triggered MM cell death; the AMPK inhibitor, dorsomorphin, partially mitigated the OB-induced MM cell death, suggesting further impairment of MM cells by AMPK activation. Conclusions In sharp contrast to MM growth enhancement with activation of the TAK1-Pim-2 pathway by BMSCs and osteoclasts, OBs with mineralized nodule formation are able to induce apoptosis along with inhibition of the Sp1-TAK1-Pim-2-mediated prosurvival pathways and thereby impairing PGC-1a-driven energy production and metabolism."

Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation • CASP8 • DKK1 • IRF4 • MYC

Terameprocol in Treating Patients With Recurrent High Grade Glioma (clinicaltrials.gov) - P1; N=23; Suspended; Sponsor: Sidney Kimmel Comprehensive Cancer Center; Initiation date: Feb 2016 ➔ Jul 2017; Trial primary completion date: Dec 2019 ➔ Dec 2021

Trial initiation date • Trial primary completion date • Biosimilar • Oncology

The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2. (PubMed, J Mol Med (Berl)) - "Sp1 binding site on the IGFBP2 promoter is required for RAD001- and M4N-induced downregulation. High IGFBP2 histoscore in endometrial cancer portends a poor prognosis."

Journal

A progressive auto-amplification loop in TAK1 expression and activation in myeloma cells (IMW 2019) - "...The TAK1 inhibitor LLZ1640-2 or TAK1 gene silencing reduced the expression of Sp1, a critical transcription factor for MM growth and survival; the Sp1 inhibitor terameprocol reduced TAK1 levels in MM cells...Besides, TAK1 inhibition reduced VCAM-1 expression in BMSCs in cocultures with MM cells, and impaired MM cell adhesion onto BMSCs to suppress RANKL expression and IL-6 production by BMSCs. Therefore, TAK1 plays a pivotal role in tumor progression and bone destruction in MM, and is regarded as an important therapeutic target for MM."

IO Biomarker

CDK4/6 Inhibition Suppresses Myeloma Cell Growth and Viability via Perturbation of E2F Proliferative Program (IMW 2019) - "...We targeted TF SP1 with Terameprocol, inhibitor of DNA binding activity and a peptide to disrupt the E2F1-DP1 heterodimerization responsible for the E2F transcription for successful inhibition of MM cell growth and viability, and the effect was augmented in presence of inhibitors of enhancers, like BRD4 inhibitor JQ1...Thus, we investigated the combination of CDK4/6 inhibitor Palbociclib with low JQ1 doses and saw profound effects on E2F promoter driven transcription, and a highly synergistic effect on growth and survival in cell lines and primary MM cells from newly diagnosed and relapsed patients...These implicate the existence of a sequestered cellular function by promoter and enhancer driven processes providing non-overlapping vulnerabilities. Simultaneous targeting of these processes using clinically applicable agents can synergistically impair the myeloma proliferative program, with potential for development of a promising therapeutic strategy."

DUAL-TARGETING OF PROMOTER AND ENHANCER DRIVEN PROCESSES SUPPRESSES MYELOMA CELL GROWTH AND VIABILITY VIA PERTURBATION OF THE MYELOMA PROLIFERATIVE PROGRAM. (EHA 2019) - "...We have further gone on to target TFs SP1 with a small molecule inhibitor Terameprocol which inhibits its DNA binding activity and a cell-permeable peptide to disrupt the heterodimerization of E2F1 with its partner DP1 responsible for the E2F transcriptional activity...Therefore, we investigated the combination of CDK4/6 inhibitor Palbociclib with low doses of JQ1 and observed a profound effects on E2F promoter driven transcriptional activity, and a highly synergistic effect on growth and survival in a large panel of cell lines and primary MM cells from newly diagnosed and relapsed patients...Importantly, the combination regimen had no significant effect on healthy donor PBMCs activated with PHA, suggesting a favorable therapeutic index.Conclusion These data implicate the existence of a sequestered cellular function by promoter and enhancer driven processes providing non-overlapping vulnerabilities. Simultaneous targeting of these processes using clinically applicable..."