Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

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Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) Kinases Promote Human T Helper 1 Cell Differentiation

Journal of Biological Chemistry ◽

10.1074/jbc.m112.361709 ◽

2012 ◽

Vol 288 (5) ◽

pp. 3048-3058 ◽

Cited By ~ 15

Author(s):

Johanna Tahvanainen ◽

Minna K. Kyläniemi ◽

Kartiek Kanduri ◽

Bhawna Gupta ◽

Hanna Lähteenmäki ◽

...

Keyword(s):

Murine Leukemia Virus ◽

Integration Site ◽

Leukemia Virus ◽

Moloney Murine Leukemia Virus ◽

T Helper ◽

T Helper 1 ◽

Proviral Integration ◽

Proviral Integration Site ◽

Pim Kinases ◽

Murine Leukemia

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PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma

Scientific Reports ◽

10.1038/s41598-021-85289-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Raoud Marayati ◽

Laura L. Stafman ◽

Adele P. Williams ◽

Laura V. Bownes ◽

Colin H. Quinn ◽

...

Keyword(s):

Integration Site ◽

Leukemia Virus ◽

Single Agent ◽

Xenograft Model ◽

Disease Recurrence ◽

Moloney Murine Leukemia Virus ◽

The Past ◽

Proviral Integration Site ◽

Pim Kinases ◽

Resistance To Chemotherapy

AbstractDespite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54–80% of patients developing resistance to chemotherapy after 4–5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.

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Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study

International Journal of Molecular Sciences ◽

10.3390/ijms20215410 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5410 ◽

Cited By ~ 2

Author(s):

Qingqing Chen ◽

Yan Wang ◽

Shanshan Shi ◽

Kaihang Li ◽

Ling Zhang ◽

...

Keyword(s):

Molecular Dynamics ◽

Murine Leukemia Virus ◽

Integration Site ◽

Leukemia Virus ◽

Moloney Murine Leukemia Virus ◽

Proviral Integration ◽

Interaction Mechanisms ◽

Proviral Integration Site ◽

Pim Kinases ◽

Murine Leukemia

Based on the up-regulation of the proviral integration site of the Moloney murine leukemia virus (Pim) kinase family (Pim1, 2, and 3) observed in several types of leukemias and lymphomas, the development of pan-Pim inhibitors is an attractive therapeutic strategy. While only PIM447 and AZD1208 have entered the clinical stages. To elucidate the interaction mechanisms of three Pim kinases with PIM447 and AZD1208, six Pim/ligand systems were studied by homology modeling, molecular docking, molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy calculation. The residues of the top group (Leu44, Val52, Ala65, Lys67, and Leu120 in Pim1) dominated the pan-Pim inhibitors binding to Pim kinases. The residues of the bottom group (Gln127, Asp128, and Leu174 in Pim1) were crucial for Pims/PIM447 systems, while the contributions of these residues were decreased sharply for Pims/AZD1208 systems. It is likely that the more potent pan-Pim inhibitors should be bound strongly to the top and bottom groups. The residues of the left, right and loop groups were located in the loop regions of the binding pocket, however, the flexibility of these regions triggered the protein interacting with diverse pan-Pim inhibitors efficiently. We hope this work can provide valuable information for the design of novel pan-Pim inhibitors in the future.

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New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation

Molecules ◽

10.3390/molecules26040867 ◽

2021 ◽

Vol 26 (4) ◽

pp. 867

Author(s):

Bruno Oyallon ◽

Marie Brachet-Botineau ◽

Cédric Logé ◽

Thomas Robert ◽

Stéphane Bach ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Cancer Progression ◽

Kinase Inhibitors ◽

Integration Site ◽

Leukemia Virus ◽

Biological Evaluation ◽

Design Synthesis ◽

Proviral Integration Site ◽

Quinoxaline Derivatives

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.

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