Pim-1 Kinase Research Articles

Identification of Pim-1 Kinase Inhibitors by Pharmacophore Model, Molecular Docking-based Virtual Screening, and Biological Evaluation.

This study aimed at screening and development of Pim-1 inhibitors as anticancer agent. Pim-1, a member of the Ser/Thr kinase family, plays a crucial role in cell proliferation and is being regarded as a promising target for cancer therapeutics. The present work focused on screening more potent Pim-1 inhibitors by in-silico method and biological evaluation. To identify more potent Pim-1 inhibitors, a GALAHAD pharmacophore model was constructed based on nine known Pim-1 inhibitors and followed by in silico screening including pharmacophore and molecular docking-based virtual screening. The hit compounds were further assessed the Pim-1, 2, and 3 kinase activities and the anticancer inhibition property against human myeloma RPMI-8226 and U266 cells using cytotoxicity studies. Based on Qfit value (from pharmacophore), docking score and clustering analysis, six compounds including C445_0268, C470_0769, 4456_0744, 0806_0325, G395_1510 and V023_3227 were hit. Binding mode analysis showed that hydrogen bond, hydrophobic and π-π stacking interactions dominated the bindings of these compounds to Pim-1. The further biological evaluation indicated that compounds C445_0268 and C470_0769 possessed excellent pan-Pim kinase activities and inhibited the growths of RPMI-8226 and U266 cell lines with IC50 values lower than 3.75 μM. We reported a series of Pim-1 small molecule inhibitors that could serve as the lead compounds to develop new targeted anticancer therapeutics.

Synthesis of 2-Oxoquinoline Derivatives as Dual Pim and mTORC Protein Kinase Inhibitors.

Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-Bromo (GRG-1-34, 6e), 4-Chloro (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1-34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 hours after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.

PIM1/STAT3 axis: a potential co-targeted therapeutic approach in triple-negative breast cancer.

Triple-negative breast cancer lacks an expression of ER, PR, and Her-2, has a poor prognosis, and there are no target therapies available. Therapeutic options to treat TNBC are limited and urgently needed. Strong evidence indicates that molecular signaling pathways have a significant function to regulate biological mechanisms and their abnormal expression endows with the development of cancer. PIM kinase is overexpressed in various human cancers including TNBC which is regulated by various signaling pathways that are crucial for cancer cell proliferation and survival and also make PIM kinase as an attractive drug target. One of the targets of the STAT3 signaling pathway is PIM1 that plays a key role in tumor progression and transformation. In this review, we accumulate the current scenario of the PIM-STAT3 axis that provides insights into the PIM1 and STAT3 inhibitors which can be developed as potential co-inhibitors as prospective anticancer agents.

P602. Do Antipsychotics Suppress Cancer initiation? Identification of Novel off Target Effects of Typical Antipsychotics Using Epidemiology, Bioinformatics, and Protein-Kinase Activity

Schizophrenia is a devastating psychiatric disorder that has a global prevalence of 1%. Interestingly, cancer rates in schizophrenia are lower than the general population. Previous epidemiological studies of cancer rates in schizophrenia did not fully account for confounding variables such as smoking and substance abuse. We sought to confirm lower cancer rates in schizophrenia and explore mechanisms responsible for this unexpected observation. We hypothesize that typical antipsychotics are competitive inhibitors of PIM kinases.

Stabilization of PIM Kinases in Hypoxia Is Mediated by the Deubiquitinase USP28.

Proviral integration sites for Moloney murine leukemia virus (PIM) kinases are upregulated at the protein level in response to hypoxia and have multiple protumorigenic functions, promoting cell growth, survival, and angiogenesis. However, the mechanism responsible for the induction of PIM in hypoxia remains unknown. Here, we examined factors affecting PIM kinase stability in normoxia and hypoxia. We found that PIM kinases were upregulated in hypoxia at the protein level but not at the mRNA level, confirming that PIMs were upregulated in hypoxia in a hypoxia inducible factor 1-independent manner. PIM kinases were less ubiquitinated in hypoxia than in normoxia, indicating that hypoxia reduced their proteasomal degradation. We identified the deubiquitinase ubiquitin-specific protease 28 (USP28) as a key regulator of PIM1 and PIM2 stability. The overexpression of USP28 increased PIM protein stability and total levels in both normoxia and hypoxia, and USP28-knockdown significantly increased the ubiquitination of PIM1 and PIM2. Interestingly, coimmunoprecipitation assays showed an increased interaction between PIM1/2 and USP28 in response to hypoxia, which correlated with reduced ubiquitination and increased protein stability. In a xenograft model, USP28-knockdown tumors grew more slowly than control tumors and showed significantly lower levels of PIM1 in vivo. In conclusion, USP28 blocked the ubiquitination and increased the stability of PIM1/2, particularly in hypoxia. These data provide the first insight into proteins responsible for controlling PIM protein degradation and identify USP28 as an important upstream regulator of this hypoxia-induced, protumorigenic signaling pathway.

Synthesis of Fused Quinoline Derivatives With Antiproliferative Activities and Tyrosine Kinases, Pim-1 Kinase Inhibitions.

Cyclohexan-1,3-dione (1) reacted with either 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2a) or diethyl 3-amino-2-cyanopent-2-enedioate (2b) to give the 5,6,7,8-tetrahydronaphthalene derivatives 3a and 3b, respectively. The latter compounds underwent further heterocyclization reactions to give the thieno[2',3':5,6]benzo[1,2-e][1,3]oxazine derivatives. On the other hand, the reaction of compound 1 with trichloroacetonitrile afforded the (2,2,2-trichloroethylidene)cyclohexane derivative 14. The latter underwent a series of reactions to produce 2,3,6,7-tetrahydroquinazoline, dihydrothieno[2,3-h]isoquinoline, octahydrobenzo[h]quinazoline and dihydrothieno[2,3-h]isoquinoline derivatives. The synthesized compounds were tested toward six cancer cell lines where most of them gave high inhibitions with c-Met enzymatic activity, with tyrosine kinases and Pim-1 inhibitions. The results obtained will encourage further work through such compounds to produce optimized anticancer agents.

Targeting Host PIM Protein Kinases Reduces Mayaro Virus Replication.

Mayaro virus (MAYV) manipulates cell machinery to successfully replicate. Thus, identifying host proteins implicated in MAYV replication represents an opportunity to discover potential antiviral targets. PIM kinases are enzymes that regulate essential cell functions and also appear to be critical factors in the replication of certain viruses. In this study we explored the consequences of PIM kinase inhibition in the replication of MAYV and other arboviruses. Cytopathic effects or viral titers in samples from MAYV-, Chikungunya-, Una- or Zika-infected cells treated with PIM kinase inhibitors were evaluated using an inverted microscope or plaque-forming assays. The expression of viral proteins E1 and nsP1 in MAYV-infected cells was assessed using an immunofluorescence confocal microscope or Western blot. Our results revealed that PIM kinase inhibition partially prevented MAYV-induced cell damage and also promoted a decrease in viral titers for MAYV, UNAV and ZIKV. The inhibitory effect of PIM kinase blocking was observed for each of the MAYV strains tested and also occurred as late as 8 h post infection (hpi). Finally, PIM kinase inhibition suppressed the expression of MAYV E1 and nsP1 proteins. Taken together, these findings suggest that PIM kinases could represent an antiviral target for MAYV and other arboviruses.

In silico design of novel anticancer drugs with amino acid and carbohydrate building blocks to inhibit PIM kinases

ABSTRACT PIM-1 is a serine-threonine kinase mainly expressed in tissues like the Thymus, spleen, bone marrow, and liver. Overexpression of PIM kinases occurs in various types of human tumours, such as lymphomas, prostate cancer, and oral cancer. As a result, the design of drugs to inhibit PIM-1 in cancerous cells has attracted much attention in recent years. This study aimed to design the alternative inhibitors for PIM-1 kinase, which are based on carbohydrates and amino acids and are expected to be non-toxic with the same chemotherapeutic effects as the traditional known anticancer drugs. The combinatorial use of quantum mechanics (QM) and molecular dynamic simulation (MD) has enabled us to precisely predict the inhibition of PIM-1 kinase by the novel designed drugs and compare them with the recently synthesized chemotherapeutic drugs such as DBC (Table 1). All designed structures were optimized at the B3LYP/6-311++G(d,p) level. The designed structure UNK4 (Table 1) was the most similar structure to DBC in terms of volumes, areas, and electrostatic potential map to DBC. The results obtained in this research represented that UNK4, with the building blocks of amino acid and cyclic carbohydrates could be considered an alternative anticancer drug for DBC.

PIM2 kinase has a pivotal role in plasmablast generation and plasma cell survival, opening up novel treatment options in myeloma

AbstractThe differentiation of B cells into plasmablasts (PBs) and then plasma cells (PCs) is associated with extensive cell reprogramming and new cell functions. By using specific inhibition strategies (including a novel morpholino RNA antisense approach), we found that early, sustained upregulation of the proviral integrations of Moloney virus 2 (PIM2) kinase is a pivotal event during human B-cell in vitro differentiation and then continues in mature normal and malignant PCs in the bone marrow. In particular, PIM2 sustained the G1/S transition by acting on CDC25A and p27Kip1 and hindering caspase 3–driven apoptosis through BAD phosphorylation and cytoplasmic stabilization of p21Cip1. In PCs, interleukin-6 triggered PIM2 expression, resulting in antiapoptotic effects on which malignant PCs were particularly dependent. In multiple myeloma, pan-PIM and myeloid cell leukemia-1 (MCL1) inhibitors displayed synergistic activity. Our results highlight a cell-autonomous function that links kinase activity to the newly acquired secretion ability of the PBs and the adaptability observed in both normal and malignant PCs. These findings should finally prompt the reconsideration of PIM2 as a therapeutic target in multiple myeloma.

Novel synthesis of pyran-3-hydrazide derivatives and their uses to the synthesis hydrazide-hydrazone, pyrazole and thiazole derivatives with anticancer activities

ABSTRACT. The multi-component reaction of ethyl acetoacetate with each of malononitrile (3) benzaldehyde (1) in ethanol containing triethylamine gave the ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (4). The latter compound reacted with hydrazine hydrate to give the hydrazide derivative 6. Compound 6 underwent a series of hetero-cyclization reactions to give pyrzole, hydraide-hydrazone, thiazole derivatives. The produced compounds tested against cancer cell lines six cancer cell lines and showed that compounds 8b, 10b, 11a, 17a, 21 and 24a were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases and Pim-1 kinase showed that compounds 10b, 21 and 24a were the most potent of the tested compounds and compounds 10a, 11a and 17a were of the highest inhibitions toward Pim-1 kinase. The high inhibitions of most of the tested compounds toward the selected cancer cell lines and the tyrosine kinases encourage for future work to be done.
 
 KEY WORDS: Hydrazide, Thiophene, Pyrazole, Pyran, Cytotoxicity, Tyrosine kinases
 
 Bull. Chem. Soc. Ethiop. 2021, 35(3), 573-586. 
 DOI: https://dx.doi.org/10.4314/bcse.v35i3.9

TARGETTING THE 3BGQ - PIM1 KINASE INTERACTION WITH A SERIES OF NOVEL DITHIOCARBAMATE SUBSTITUTED 2-OXOINDOLE DERIVATIVES- IN SILICO STUDIES

Objective: Cancer is the major cause of mortality in most of the developing countries. Enormous chemotherapeutic agents developed are still need improvements in survival rates and quality of life for cancer patients. Pro-viral Integration site of Moloney murine leukemia virus (PIM1) is a family of serine/threonine kinase, regulated by calcium/calmudulin have been identified as a unique molecular target in oncogenesis. PIM1 has significant role in cell cycle regulation, cell survival, apoptosis, cellular senescence, drug resistance and it is emerging as a potential biomarker in number of human malignancies. Today many interesting PIM1 inhibitors are developed and few withdrawn from phase1 and 2 clinical trials, due to lack of bioavailability and toxicity. Hence the purpose of the present study is to develop more potent and less toxic compounds. Material and Method: A series of novel 2-oxindoles with dithiocarbamates were designed as PIM1 inhibitors. All molecules were subjected to Molsoft, Molinspiration, Swiss ADME and pkCSM to predict their molecular properties which are important for drug candidate. Further, in order to find the binding affinity of designed molecules with PIM1 kinase protein and to rationalize their anticancer activity, molecular docking study was performed. Result and Discussion: Results revealed that all designed compounds fulfilled the criteria for good oral bioavailability, low toxicity and the potential inhibitory activities. All of them were docked into active site of PIM1 kinase with AutoDock Vina software. In conclusion, according to the binding energy values, compound 16 and 24 showed equivalent dock score -9.7 kcal/mol which are comparable with previously reported compounds AZ1208 and SGI 1776. This finding will help the researchers in the design of a better drug for the treatment of cancer.

In silico study for the identification of potential compounds as PIM-1 kinase inhibitors

PIM kinases are a group of serine/threonine kinases that are classified into three isoforms: PIM1, PIM2, and PIM3. Pim-1 kinase is a critical enzyme that is involved in cell growth, cell survival, differentiation, apoptosis, senescence and drug resistance. The PUBMED database has been taken for the screening of PIM-1 kinase inhibitor. This database, further, screened by Lipinski Rule of five, HTVS, standard precision (SP), and extra precision (XP) methodologies. 2OJF protein of PIM-1 kinase was taken for molecular docking. The compound 1a showed good docking scores, SP = −7.244 and XP = −8.6, whereas 1i showed minimal SP and XP scores. These studies may be used for the further development of potential compounds against PIM-1 kinase.

Spectroscopic Identification, Structural Features and Molecular Docking Studies on 5-(4-Propoxybenzylidene)-2-[3-(4-chlorophenyl)-5-[4(propan-2-yl) phenyl-4,5-dihydro- 1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one using Pim-1 Kinase Cancer Protein

A comprehensive investigation of the molecular structure, electronic properties and vibrational spectra of 5-(4-propoxybenzylidene)-2-[3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1Hpyrazol- 1-yl]-1,3-thiazol-4(5H)-one have been studied. Many natural and/or synthetic compounds contain, thiazole which are attractive compounds found in the building of numerous natural products and certain pharmaceutical agents. To understand the molecular-orbital interaction and structural investigation of the title compound, the density functional theory (DFT) calculation has been carried out using B3LYP/6-31G and 6-311G basis sets combination. The experimental FT-IR, FT-Raman spectral data along with theoretical quantum chemical calculation were investigated. For potential energy distributions (PED) analysis, the VEDA 4 program is utilized to do comparative frequency assignments. With the optimized structures, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) energies, molecular electrostatic potential (MEP) and natural bond orbital (NBO) were applied to describe the chemical reactivity.The electron density interactions distributed in space, which exist within these compounds are analyzed by different topological methods namely, atom in molecule (AIM), localized orbital locator (LOL), electron localization function (ELF) and the reduced density gradient (RDG). Finally, the molecular docking studies of the title compound for potent Pim-1 kinase cancer PDB ID: 3A99, 1GJ8, 1XQZ was investigated using theAuto Dock program

Utilization of cyanopyridine in design and synthesis of first-in-class anticancer dual acting PIM-1 kinase/HDAC inhibitors

Herein, we report design and synthesis of twenty-one dual PIM-1/HDAC inhibitors utilizing 3-cyanopyridines as a novel cap moiety linked with aliphatic /aromatic linker bearing carboxylic acid 3a-g, hydroxamic acid 4a-g or 2-aminoanilide moieties 5a-g as zinc-binding group. Most of the target hybrids revealed promising growth inhibition according to one dose NCI protocol against 60 cancer cell lines. Meanwhile, hydroxamic acids 4b, 4d and 4e displayed strong and broad-spectrum activity against nine tumor subpanels tested (GI50 0.176–8.87 μM); 4d displayed strong antiproliferative activity with GI50 ≤ 3 μM against different cancer cell lines (GI50 range from 0.325 to 2.9 μM). Furthermore, 4a, 4d-4g and 5f manifested a high inhibitory activity against HDACs 1 and 6 isozymes; 4g, displayed potent HDAC 1 and 6 inhibitory activity (45.01 ± 2.1 and 19.78 ± 1.1 nM) more than the reference SAHA (51.54 ± 2.4 and 21.38 ± 1.2 nM, respectively), while 4f was more potent (30.09 ± 1.4 nM) than SAHA against HDAC 1 and less potent (30.29 ± 1.7 nM) than SAHA against HDAC 6. Hybrids 4b, 4d, 4e and 4f exhibited potent PIM-1 inhibitory activity; 4d showed comparable activity to quercetin (IC50 of 343.87 ± 16.6 and 353.76 ± 17.1 nM, respectively); it exhibited pre G1 apoptosis and arrest cell cycle at G2/M phase. Moreover, it revealed good binding into pocket of HDACs 1,6 and PIM-1 kinase enzymes with good correlation with biological results. Moreover, 4b, 4d and 4e had reasonable drug-likeness properties according to Lipinski’s rule. However, multitarget inhibitor of PIM-1/HDAC is a promising strategy in anticancer drug discovery; the most potent hybrids require further in vivo and clinical investigations.

Multi-Component Reactions of Cyclohexan-1,3-dione: Synthesis of Fused Pyran, Pyridine, Thiophene and Pyrazole Derivatives with c-Met, Anti-Proliferative Activities.

Recently, products of Multi-Component Reactions (MCR's) acquired special attention due to their wide range of pharmacological activities especially therapeutic activities. In the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR's were found. This work aims to synthesize target molecules not only possess anti-tumour activities but also c-Met and prostate cancer inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione through its multi-component reactions to produce anticancer target molecules. Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused pyran, pyridine and thiophene derivatives. The anti-proliferative activity of the newly synthesized compounds among the synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions toward c-Met kinase and prostate cancer cell line were studied. Antitumor evaluations toward seventeen cancer cell lines subpanel, for certain compounds, were also demonstrated according to the diseases. Pim-1 kinase inhibitions of the most active compounds were also measured. Anti-proliferative evaluations, c-Met and Pim-1 kinase inhibitions were performed for most of the synthesized compounds where the varieties of substituent through the aryl ring and the heterocyclic ring afforded compounds with high activities. Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b, 25b and 26b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cells showed that the presence of the electronegative Cl group within the molecule were responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.

Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies.

The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.

Abstract P223: Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors

Abstract Background: Elevated expression of PIM kinases in various solid and hematologic malignancies is correlated with increased cell survival and reduced apoptosis, implicating inhibition of PIM kinases as attractive targets for disruptive therapy. TP-3654 is an oral, small molecule, investigational PIM kinase inhibitor with favorable selectivity against PIM-1 over other kinases. TP-3654 is currently being evaluated in a phase 1 first-in-human study in patients (pts) with advance solid tumors (NCT03715504). Methods: Pts with advanced metastatic, progressive, or unresectable solid tumors refractory or intolerant of established therapies were treated with TP-3654. Pts took TP-3645 orally once (QD) or twice (BID) daily in a 28-day dosing cycle until unacceptable toxicity or disease progression. Escalating dose levels of TP-3654 were evaluated using a 3+3 design. The primary objective was to determine maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included establishing the pharmacokinetic (PK) profile of oral TP-3654 and any evidence of antitumor activity. An exploratory objective was to study predictive biomarkers in tumor tissues and mechanism-based pharmacodynamic activity in peripheral blood mononuclear cells (PBMCs). Results: As of 31 May 2021, 22 pts were treated with TP-3654 at 480 mg QD (n=3), 720 mg QD (n=3), 1080 mg QD (n=4), 1440 mg QD (n=3), 720 mg BID (n=3), and 960 mg BID (n=6). Median age of 58 years (range: 20–72), 59% (13/22) pts male, and 86% (19/22) pts received ≥3 lines of prior therapy. Median treatment duration is 2 cycles (range: 0.1–24) and 6 pts received treatment for ≥4 cycles. Two pts remain on active study treatment. No DLT was observed. The most common treatment-emergent adverse events (TEAEs) reported in ≥20% of pts were vomiting, diarrhea, nausea, and abdominal pain. No related myelosuppressive AEs were reported. Fifty percent (11/22) of pts reported 18 Grade ≥3 TEAEs, of which only one (alanine aminotransferase increased) was considered related to TP-3654. No related, serious AEs were reported. Two TEAEs resulted in a fatal outcome (acute kidney injury, completed suicide); neither were related to TP-3654. Best response is stable disease (SD) in 67% (10/15) evaluable pts, SD for ≥ 16 weeks in 5 pts, best reduction of tumor size from baseline is -22%. TP-3654 plasma exposure increased with doses up to 1080 mg QD; the BID regimen at the 720 mg dose achieved greater plasma exposure than the 1440 mg QD dosing regimen. Reduced phosphorylation of PIM-1 downstream signal protein pBAD was observed in isolated PBMCs, predominantly in pts with prolonged clinical benefit. Conclusions: Preliminary data suggest that TP-3654 is tolerated as a monotherapy up to 960 mg BID in pts with heavily pretreated, relapsed, and refractory solid tumors. No DLT was observed and MTD was not reached. PK data indicate that the BID dose regimen achieved better plasma exposure than the QD regimen at higher doses. TP-3654 has shown target-specific inhibition of PIM-1 in pts. Updated data will be presented. Citation Format: Ignacio Garrido-Laguna, Patrick M. Dillon, Sujan Kabir, Jian Mei, Mark L. Wade, Huyuan Yang, Carl Stapinski, Jason M. Foulks, Steven L. Warner, Clifford Whatcott, Claudia Lebedinsky, Siqing Fu. Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P223.

Pyrazolopyrimidines as anticancer agents: A review on structural and target-based approaches

Pyrazolopyrimidine scaffold is one of the privileged heterocycles in drug discovery. This scaffold produced numerous biological activities in which anticancer is important one. Previous studies showed its importance in interactions with various receptors such as growth factor receptor, TGFBR2 gene, CDK2/cyclin E and Abl kinase, adenosine receptor, calcium-dependent Protein Kinase, Pim-1 kinase, Potent Janus kinase 2, BTK kinase, P21-activated kinase 1, extracellular signal-regulated kinase 2, histone lysine demethylase and Human Kinesin-5. However, there is a need of numerous studies for the discovery of target based potential compounds. The structure activity relationship studies may help to explore the generation of potential compounds in short time period. Therefore, in the present review we tried to explore the structural aspects of Pyrazolopyrimidine with their structure activity relationship against various targets for the development of potential compounds. The current review is the compilation of significant advances made on Pyrazolopyrimidines reported between 2015 and 2020.

PDGF-BB promotes vascular smooth muscle cell migration by enhancing Pim-1 expression via inhibiting miR-214.

BackgroundSeveral studies have indicated that the platelet-derived growth factor/platelet-derived growth factor receptor (PDGF/PDGFR) pathway is involved in the process of atherosclerosis. However, its underlying mechanism remains to be further elucidated. Serine/threonine-protein kinase pim-1 (Pim-1), a member of serine/threonine-specific kinases, is a pro-oncogene published to be related to cell proliferation, apoptosis, and metastasis of cancer cells. Whether Pim-1 is involved in PDGF/PDGFR pathway-mediated coronary atherosclerotic heart disease remains to be elucidated.MethodsWe established a cell model of PDGF-BB-stimulated smooth muscle cells using A7r5 cells. Transwell assay was used to detect the potential of cell migration and invasion. The targeted regulation of Pim-1 by miR-214 was confirmed by luciferase assay. Rescue experiments were performed to determine the role of the PDGF-BB/miR-214/Pim-1 axis on the cell migration of smooth muscle cells by including PDGF-BB treatment, and the overexpression of miR-214 and Pim-1. Quantitative polymerase chain reaction (qPCR) was used to examine the gene expression and western blot was performed to detect the protein expression.ResultsOur data indicated that PDGF-BB could effectively enhance smooth muscle cell migration. We also showed Pim-1 was a target of miR-214 in A7r5 cells. The expression of Pim-1 was shown to be upregulated by PDGF-BB via suppression of the expression of miR-214. Moreover, overexpression miR-214 inhibited PDGF-BB-stimulated Pim-1 expression and smooth muscle cell migration via modulating epithelial-mesenchymal transition (EMT), but no change on cell cycle. However, overexpression of Pim-1 reversed miR-214-blocked cell migration by promoting the activation of the STAT3, AKT, and ERK signaling pathways.ConclusionsOur data suggested that the PDGF/miR-214/Pim-1 axis could be a potential target for coronary atherosclerotic heart disease.

Feedback Loop Regulation between Pim Kinases and Tax Keeps Human T-Cell Leukemia Virus Type 1 Viral Replication in Check

The Pim family of serine/threonine kinases promote tumorigenesis by enhancing cell survival and inhibiting apoptosis. Three isoforms exist, Pim-1, -2, and -3, that are highly expressed in hematological cancers, including Pim-1 in adult T-cell leukemia (ATL). Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of ATL, a dismal lymphoproliferative disease known as adult T-cell leukemia. The HTLV-1 virally encoded oncogene Tax promotes CD4+ T-cell transformation through disruption of DNA repair pathways and activation of survival and cellular proliferation pathways. In this study, we found Tax increases the expression of Pim-1 and Pim-3, while decreasing Pim-2 expression. Furthermore, we discovered that Pim-1, -2, and -3 bind Tax protein to reduce its expression thereby creating a feedback regulatory loop between these two oncogenes. The loss of Tax expression triggered by Pim kinases led to loss in Tax-mediated transactivation of the HTLV-1 long terminal repeat (LTR) and reductions in HTLV-1 virus replication. Because Tax is also the immunodominant cytotoxic T cell lymphocytes (CTL) target, our data suggest that Pim kinases may play an important role in immune escape of HTLV-1-infected cells. IMPORTANCE The Pim family of protein kinases have established pro-oncogenic functions. They are often upregulated in cancer; especially leukemias and lymphomas. In addition, a role for Pim kinases in control of virus expression and viral latency is important for Kaposi sarcoma-associated herpesvirus (KSHV) and human immunodeficiency virus type 1 (HIV-1). Our data demonstrate that HTLV-1 encodes viral genes that promote and maintain Pim kinase activation, which in turn may stimulate T-cell transformation and maintain ATL leukemic cell growth. HTLV-1 Tax increases expression of Pim-1 and Pim-3, while decreasing expression of Pim-2. In ATL cells, Pim expression is maintained through extended protein half-life and heat shock protection. In addition, we found that Pim kinases have a new role during HTLV-1 infection. Pim-1, -2, and -3 can subvert Tax expression and HTLV-1 virus production. This may lead to partial suppression of the host immunogenic responses to Tax and favor immune escape of HTLV-1-infected cells. Therefore, Pim kinases have not only pro-oncogenic roles but also favor persistence of the virus-infected cell.