Publications by authors named "Brendan Frett"

34 Publications

Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.

Eur J Med Chem 2021 Apr 9;216:113265. Epub 2021 Feb 9.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.
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http://dx.doi.org/10.1016/j.ejmech.2021.113265DOI Listing
April 2021

Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered by a Fragment Optimization Approach.

ChemMedChem 2021 Feb 8. Epub 2021 Feb 8.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non-small-cell lung cancers. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA-driven matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found to be active on RET in a biochemical assay, but reduced cell viability in non-RET-driven cell lines (EC =1 and 3 μM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8 p, which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC =5.92 μM, LC-2/ad EC =0.016 μM, RET IC =0.000326 μM).
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http://dx.doi.org/10.1002/cmdc.202100013DOI Listing
February 2021

Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.

Eur J Med Chem 2020 Nov 6;206:112691. Epub 2020 Aug 6.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address:

Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
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http://dx.doi.org/10.1016/j.ejmech.2020.112691DOI Listing
November 2020

Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression.

Eur J Med Chem 2020 Oct 12;203:112589. Epub 2020 Jul 12.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Electronic address:

Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
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http://dx.doi.org/10.1016/j.ejmech.2020.112589DOI Listing
October 2020

ProteoViz: a tool for the analysis and interactive visualization of phosphoproteomics data.

Mol Omics 2020 08 29;16(4):316-326. Epub 2020 Apr 29.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street (slot 516), Little Rock, AR 72205-7199, USA.

Quantitative proteomics generates large datasets with increasing depth and quantitative information. With the advance of mass spectrometry and increasingly larger data sets, streamlined methodologies and tools for analysis and visualization of phosphoproteomics are needed both at the protein and modified peptide levels. To assist in addressing this need, we developed ProteoViz, which includes a set of R scripts that perform normalization and differential expression analysis of both the proteins and enriched phosphorylated peptides, and identify sequence motifs, kinases, and gene set enrichment pathways. The tool generates interactive visualization plots that allow users to interact with the phosphoproteomics results and quickly identify proteins and phosphorylated peptides of interest for their biological study. The tool also links significant phosphosites with sequence motifs and pathways that will help explain the experimental conditions and guide future experiments. Here, we present the workflow and demonstrate its functionality by analyzing a phosphoproteomic data set from two lymphoma cell lines treated with kinase inhibitors. The scripts and data are freely available at and via the ProteomeXchange with identifier PXD015606.
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http://dx.doi.org/10.1039/c9mo00149bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423749PMC
August 2020

Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology.

J Med Chem 2020 05 28;63(9):4506-4516. Epub 2020 Apr 28.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy.

RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed a selective inhibitory profile and an inhibitory concentration 50 (IC) of <0.003 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901654PMC
May 2020

Correction: One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

Chem Commun (Camb) 2020 Feb 7;56(14):2210. Epub 2020 Feb 7.

College of Pharmacy, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.

Correction for 'One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction' by Jie Lei et al., Chem. Commun., 2020, DOI: .
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http://dx.doi.org/10.1039/d0cc90063jDOI Listing
February 2020

One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

Chem Commun (Camb) 2020 Feb 23;56(14):2194-2197. Epub 2020 Jan 23.

College of Pharmacy, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.
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http://dx.doi.org/10.1039/c9cc08220dDOI Listing
February 2020

Structural Characterization of the Aurora Kinase B "DFG-flip" Using Metadynamics.

AAPS J 2019 12 18;22(1):14. Epub 2019 Dec 18.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.

Aurora kinase B (AKB), a Ser/Thr kinase that plays a crucial role in mitosis, is overexpressed in several cancers. Clinical inhibitors targeting AKB bind to the active DFG "in" conformation of the kinase. It would be beneficial, however, to understand if AKB is susceptible to type II kinase inhibitors that bind to the inactive, DFG "out" conformation, since type II inhibitors achieve higher kinome selectivity and higher potency in vivo. The DFG "out" conformation of AKB is not yet experimentally determined which makes the design of type II inhibitors exceedingly difficult. An alternate approach is to simulate the DFG "out" conformation from the experimentally determined DFG "in" conformation using atomistic molecular dynamics (MD) simulation. In this work, we employed metadynamics (MTD) approach to simulate the DFG "out" conformation of AKB by choosing the appropriate collective variables. We examined structural changes during the DFG-flip and determined the interactions crucial to stabilize the kinase in active and inactive states. Interestingly, the MTD approach also identified a unique transition state (DFG "up"), which can be targeted by small molecule inhibitors. Structural insights about these conformations is essential for structure-guided design of next-generation AKB inhibitors. This work also emphasizes the usefulness of MTD simulations in predicting macromolecular conformational changes at reduced computational costs.
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http://dx.doi.org/10.1208/s12248-019-0399-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905835PMC
December 2019

The Exploration of Chirality for Improved Druggability within the Human Kinome.

J Med Chem 2020 01 9;63(2):441-469. Epub 2019 Oct 9.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205 , United States.

Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00640DOI Listing
January 2020

Catalyst free, C-3 functionalization of imidazo[1,2-a]pyridines to rapidly access new chemical space for drug discovery efforts.

Chem Commun (Camb) 2018 Nov;54(92):12954-12957

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.

Multicomponent reactions (MCRs) are robust tools for the rapid synthesis of complex, small molecule libraries for use in drug discovery and development. By utilizing MCR chemistry, we developed a protocol to functionalize the C-3 position of imidazo[1,2-a]pyridine through a three component, decarboxylation reaction involving imidazo[1,2-a]pyridine, glyoxalic acid, and boronic acid.
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http://dx.doi.org/10.1039/c8cc07063fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284400PMC
November 2018

Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-]pyridine derivatives.

Tetrahedron 2018 Aug 17;74(35):4592-4600. Epub 2018 Jul 17.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, C-C bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance C-C bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl. The protocol has broad application in the construction of acetylated imidazo[1,2-]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-]pyridine building-blocks for combinatorial synthetic efforts.
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http://dx.doi.org/10.1016/j.tet.2018.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192254PMC
August 2018

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

J Med Chem 2019 02 19;62(4):1731-1760. Epub 2018 Sep 19.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205 , United States.

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875308PMC
February 2019

Synthesis of Constrained Heterocycles Employing Two Post-Ugi Cyclization Methods for Rapid Library Generation with In Cellulo Activity.

ChemistrySelect 2017 12 19;2(35):11821-11825. Epub 2017 Dec 19.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 United States

Benzimidazoles and quinoxalinones are present in the core of many pharmacologically relevant compounds. Several combinatorial methods have been developed to attach ring systems to both scaffolds for derivatization at select positions. Herein, we describe the development of novel constrained heterocyclic compounds attached to the N1 position of both benzimidazole and quinoxalinone scaffolds. Utilizing robust post-Ugi cyclization methods, including the Ugi-deprotection-cyclization (UDC) methodology, allows for efficient access to a new area of chemical space. Additionally, molecular modeling and in cellulo screening was employed to therapeutically validate the compounds formed with this method.
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http://dx.doi.org/10.1002/slct.201702179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103208PMC
December 2017

Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells.

Bioorg Med Chem 2018 08 12;26(14):3899-3908. Epub 2018 Jun 12.

Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China. Electronic address:

Colorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G/M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies.
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http://dx.doi.org/10.1016/j.bmc.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718200PMC
August 2018

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

Sci Rep 2018 02 27;8(1):3722. Epub 2018 Feb 27.

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.
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http://dx.doi.org/10.1038/s41598-018-21839-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829162PMC
February 2018

Recent advances in the development of polycyclic skeletons via Ugi reaction cascades.

Mol Divers 2018 May 16;22(2):503-516. Epub 2018 Jan 16.

Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.
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http://dx.doi.org/10.1007/s11030-017-9811-2DOI Listing
May 2018

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2.

J Clin Invest 2017 Aug 24;127(8):3075-3089. Epub 2017 Jul 24.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Accumulating evidence suggests that glioma stem cells (GSCs) are important therapeutic targets in glioblastoma (GBM). In this study, we identified NIMA-related kinase 2 (NEK2) as a functional binding protein of enhancer of zeste homolog 2 (EZH2) that plays a critical role in the posttranslational regulation of EZH2 protein in GSCs. NEK2 was among the most differentially expressed kinase-encoding genes in GSC-containing cultures (glioma spheres), and it was required for in vitro clonogenicity, in vivo tumor propagation, and radioresistance. Mechanistically, the formation of a protein complex comprising NEK2 and EZH2 in glioma spheres phosphorylated and then protected EZH2 from ubiquitination-dependent protein degradation in a NEK2 kinase activity-dependent manner. Clinically, NEK2 expression in patients with glioma was closely associated with EZH2 expression and correlated with a poor prognosis. NEK2 expression was also substantially elevated in recurrent tumors after therapeutic failure compared with primary untreated tumors in matched GBM patients. We designed a NEK2 kinase inhibitor, compound 3a (CMP3a), which efficiently attenuated GBM growth in a mouse model and exhibited a synergistic effect with radiotherapy. These data demonstrate a key role for NEK2 in maintaining GSCs in GBM by stabilizing the EZH2 protein and introduce the small-molecule inhibitor CMP3a as a potential therapeutic agent for GBM.
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http://dx.doi.org/10.1172/JCI89092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531394PMC
August 2017

Structure-based design and synthesis of imidazo[1,2-a]pyridine derivatives as novel and potent Nek2 inhibitors with in vitro and in vivo antitumor activities.

Eur J Med Chem 2017 Jan 12;126:1083-1106. Epub 2016 Dec 12.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address:

We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC = 3.0 nM) and 42g (MBM-55, IC = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.026DOI Listing
January 2017

Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.

Angew Chem Int Ed Engl 2015 Jul 30;54(30):8717-21. Epub 2015 Jun 30.

Medicinal Chemistry Division, Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, AZ 85721 (USA).

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a type II tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg(-1)  day(-1) per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0 mg kg(-1), which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.
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http://dx.doi.org/10.1002/anie.201501104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535927PMC
July 2015

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.

Eur J Med Chem 2015 Apr 28;94:123-31. Epub 2015 Feb 28.

College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA; The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. Electronic address:

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.
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http://dx.doi.org/10.1016/j.ejmech.2015.02.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666306PMC
April 2015

Metal-free, efficient hydrazination of imidazo[1,2-a]pyridine with diethyl azodicarboxylate in neutral media.

Org Biomol Chem 2015 Mar;13(10):2958-64

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.

The first example of metal-free regioselective hydrazination of imidazo[1,2-a]pyridine with diethyl azodicarboxylate is accomplished. This procedure is chemically appealing due to the high degree of functional group tolerance and efficiency in expanding the molecular diversity.
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http://dx.doi.org/10.1039/c4ob02284jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675458PMC
March 2015

Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies.

Medchemcomm 2014 Oct 11;5(10):1507-1514. Epub 2014 Aug 11.

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA; The University of Arizona Cancer Center, Tucson, Arizona 85724, USA.

Trk receptors play a key role in the development and maintenance of neuronal networks. Recent evidence suggests that the Trk family, specifically TrkA, is an important driver for tumour growth, inflammatory and neuropathic pain, and chemoresistance. Through a computational screen, a novel Trk active pharmacophore was identified and a series of pyrazine-based inhibitors were developed, which potently inhibited TrkA. Inhibitors displayed the highest activity on TrkA when screened against a small, tyrosine kinase panel and also exhibited a non-linear SAR. Predicted binding modes of the inhibitors were examined, which identified exploitable regions for future development of more advanced inhibitors.
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http://dx.doi.org/10.1039/C4MD00251BDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734651PMC
October 2014

Identification of two novel RET kinase inhibitors through MCR-based drug discovery: design, synthesis and evaluation.

Eur J Med Chem 2014 Oct 8;86:714-23. Epub 2014 Sep 8.

College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA; The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. Electronic address:

From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.
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http://dx.doi.org/10.1016/j.ejmech.2014.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666024PMC
October 2014

Selective Reduction of Halogenated Nitroarenes with Hydrazine Hydrate in the Presence of Pd/C.

Synlett 2014 Jun;25(10):1403-1408

College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA, Fax +1(520)6260794; BIO-5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd, Oro Valley, AZ 85737, USA.

A large variety of halogenated nitroarenes have been selectively reduced with hydrazine hydrate in the presence of Pd/C to give the corresponding (halogenated) anilines in good yield.
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http://dx.doi.org/10.1055/s-0033-1339025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734645PMC
June 2014

Efficient access to 2,3-diarylimidazo[1,2-a]pyridines via a one-pot, ligand-free, palladium-catalyzed three-component reaction under microwave irradiation.

Org Lett 2014 Jun 22;16(11):3016-9. Epub 2014 May 22.

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.

An expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines analogues.
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http://dx.doi.org/10.1021/ol501136eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059256PMC
June 2014

Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition.

J Med Chem 2014 Jul 25;57(14):5835-44. Epub 2014 Feb 25.

Department of Pharmacoloy and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.

The global incidence of cancer is on the rise, and within the next decade, the disease is expected to become the leading cause of death worldwide. Forthcoming strategies used to treat cancers focus on the design and implementation of multidrug therapies to target complementary cancer specific pathways. A more direct means by which this multitargeted approach can be achieved is by identifying and targeting interpathway regulatory factors. Recent advances in understanding Nek2 (NIMA related kinase 2) biology suggest that the kinase potentially represents a multifaceted therapeutic target. In this regard, pharmacologic modulation of Nek2 with a single agent may effect several mechanisms important for tumor growth, survival, progression, and metastasis. We herein review the development of Nek2 as an oncology target and provide a succinct chronology of drug discovery campaigns focused on targeting Nek2.
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http://dx.doi.org/10.1021/jm401719nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666018PMC
July 2014